Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials.

PURPOSE: To evaluate the structure-modifying and symptom efficacy, as well as safety and tolerability of oral salmon calcitonin (sCT) formulated with a 5-CNAC carrier (a molecule based on Eligen(®) technology), in osteoarthritis (OA) patients with moderate to severe knee pain and joint structural damage classified as Kellgren and Lawrence (KL)2-3. METHODS AND DESIGN: This is the combined reporting of two randomized, double-blind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of oral sCT in patients with painful knee OA with structural manifestations, enrolling 1176 and 1030 patients, respectively. Study subjects were randomized (1:1) to oral sCT 0.8 mg twice daily or placebo (PBO) for 24 months. The primary efficacy objectives were to examine the treatment effect compared to placebo on change over 24 months in joint space width (JSW) in the signal knee measured by X-ray, and to examine the change in pain and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire. Other study parameters included patient and physician global assessment, and biochemical markers of bone (CTX-I) and cartilage degradation (CTX-II). RESULTS: At the 24 month endpoint there was no statistically significant treatment effect on joint space narrowing (JSN) in any of the two studies. In CSMC021C2301 there was a treatment effect on WOMAC (sum of pain, function, stiffness, and total scores) as well as on the biomarkers of bone and joint metabolism, but due to the hierarchical testing procedure the treatment effect was not claimed statistically significant. CONCLUSIONS: The present formulation of oral sCT did not provide reproducible clinical benefits in patients with symptomatic knee OA (NCT00486434, NCT00704847).

OA phenotypes, rather than disease stage, drive structural progression--identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA.

BACKGROUND/PURPOSE: The aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI. METHODS: Data from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA). RESULTS: There was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner. CONCLUSION: These data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression.

Investigation of two novel biochemical markers of inflammation, matrix metalloproteinase and cathepsin generated fragments of C-reactive protein, in patients with ankylosing spondylitis.

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammation of the spine and the sacroiliac joints. Current markers of inflammation, such as C-reactive protein (CRP), are reflecting the production of an acute phase reactant rather than tissue specific inflammation, but the use of CRP as a diagnostic and prognostic marker for AS has not provided the sought accuracy and specificity. We hypothesized that local enzymatic activity in the disease-affected tissue, which is associated with extensive tissue turnover may, by cleavage, modify the CRP produced in the liver. These cleavage products may provide additional information on systemic inflammation as compared to that of full-length CRP. We investigated whether these CRP degradation products would provide additional diagnostic value in AS patients compared to full-length CRP. METHODS: CRP fragments were identified by mass-spectrometry. Two fragments were selected for ELISA development. One assay exclusively identified a matrix metalloproteinase (MMP) generated fragment, CRP-MMP, whereas the other assay identified a cathepsin generated fragment, CRP-CAT. Full-length CRP, CRP-MMP and CRP-CAT were measured in serum samples from 40 AS patients and 40 sex- and age-matched controls. RESULTS: Full-length CRP was not elevated in AS patients compared to controls, whereas CRP-MMP was elevated by 25% (p<0.001) and CRP-CAT by 50% (p<0.0001). The Area Under Curve of the Receiver-Operator Characteristic curve of CRP-CAT was the highest with 77%. CONCLUSIONS: MMP and cathepsin degraded CRP provided more discriminative diagnostic potential compared to that of full-length CRP in this current study. These data suggest that different pools of CRP may provide insight into the inflammation processes in AS.

Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis.

OBJECTIVE: The objective of this post hoc analysis was to investigate the effect of strontium ranelate on a cartilage degradation marker in postmenopausal women who participated in a randomized, placebo-controlled osteoporosis study. Women were stratified according to reported symptoms of osteoarthritis and to the baseline levels of a cartilage degradation marker. METHODS: The analysis included the 2617 postmenopausal women (75 years old) with osteoporosis randomized to strontium ranelate or placebo for a 36-month period. Cartilage degradation was evaluated using a validated urinary marker adjusted for creatinine (CTX-II/cr), whereas bone resorption was assessed by serum CTX-I. The presence of osteoarthritis was determined by individual interviews. RESULTS: CTX-II was significantly elevated at baseline in subjects with a history of osteoarthritis (OA+) compared to subjects who did not (OA-) (p < 0.0001), whereas CTX-I was unaffected by osteoarthritis status. Strontium ranelate caused a significant decrease from baseline in CTX-II over a 12-month period whatever the osteoarthritis status. Strontium ranelate-treated patients had a significant decrease in CTX-II compared to placebo in both OA+ and OA- groups up to 12 months, the difference remaining still significant at 36 months in patients from the OA- group (p < 0.001). CONCLUSIONS: The CTX-II profile of changes over 3 years may reflect efficacy of strontium ranelate against cartilage degradation, with an enhanced beneficial effect in subjects with early or mild clinical osteoarthritis, probably exerting its putative chondroprotective influence in early stages of the disease. Carefully controlled studies in targeted populations with early osteoarthritis are warranted to assess the role of strontium ranelate halting osteoarthritis progression.

Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD.

BACKGROUND: Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD. METHODS: This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics. RESULTS: To be expected early 2023 CONCLUSION: This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498650.

Matrix Metalloproteinase Mediated Type I Collagen Degradation - An Independent Risk Factor for Mortality in Women.

Chronic fibro-proliferative diseases are associated with nearly 45% of all deaths in the developed world. Matrix metalloproteinase (MMP) mediated remodeling of the extracellular matrix (ECM) plays an important role in disease development. Degradation of type I collagen is considered having a major role in this matter. C1M is a biomarker measuring type I collagen degradation fragments in blood. The aim of the current study was to investigate whether MMP mediated type I collagen degradation (C1M) was predictive of mortality in a large prospective cohort of Danish women aged 48-89 (n = 5855). Subjects with high serum C1M showed significant increased mortality. The adjusted three year HR was 2.02 [95% CI: 1.48-2.76] for all-cause mortality, 2.32 [95% CI: 1.51-3.56] for cancer and 1.77 [95% CI: 0.98-3.17] for cardiovascular diseases. The adjusted nine year HR was 1.50 [95% CI: 1.28-1.75] for all-cause mortality, 1.49 [95% CI: 1.16-1.90] for cancer and 1.69 [95% CI: 1.27-2.24] for cardiovascular diseases. High MMP-mediated type I collagen degradation was associated with increased mortality. Subjects with high C1M had a 2-fold increase in mortality compared to subjects with low levels of this collagen degradation product.

Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomized study.

Sodium fluoride stimulates bone formation and has been used to treat osteoporosis for decades despite debate about the antifracture efficacy. Hormone replacement therapy (HRT) results in only modest increases in bone mineral density (BMD). However, for women with low bone mass, the ideal therapy should not only inhibit bone resorption but simultaneously stimulate bone formation to increase bone mass above the fracture threshold. We thus performed a randomized, double-blind, placebo-controlled intervention study to prospectively investigate the effect of a low dose of fluoride, in combination with HRT, on BMD and biochemical markers of bone turnover. One hundred healthy postmenopausal women (60-70 yr old) were thus randomly assigned to: 1) HRT [transdermal 17beta-estradiol, releasing 50 microg/day; plus oral norethisterone acetate (NETA), 1 mg/day]; or 2) oral monofluorophosphate (MFP; equivalent to fluoride, 20 mg/day); or 3) HRT+MFP; or 4) placebo, for 96 weeks. All participants received a calcium supplement of 1000 mg/day. Sixty-eight women completed the study. We found a pronounced, linear increase in spinal BMD during treatment with HRT+MFP [11.8% (1.7% SEM)], which was significantly greater than the increase in the HRT group [4.0% (0.5% per yr); P < 0.05]. MFP produced a smaller increase [2.4% (0.6% per yr)], whereas there was no change in the placebo group [0.0% (0.5% SEM)]. Similar changes were found at the other skeletal sites (distal forearm, hip, and total body). Markers of bone formation showed a fall in the HRT group, which was significantly more pronounced than in the combined HRT+MFP group. A nonsignificant increase was found in the MFP group, whereas the placebo group showed a decrease caused by calcium treatment. The marker of bone resorption decreased significantly more in the HRT and the HRT+MFP groups than in the placebo group but tended to increase in the MFP group. In conclusion, this study shows, by use of biochemical markers of bone turnover, that bone resorption and formation may be dissociated, as a result of actions of two compounds with diverging effects on bone turnover. Furthermore, the synergistic effects of relatively low doses of the compounds suggested statistically and clinically significant increases in trabecular and probably also cortical bone. Adverse effects were relatively rare and mild.

Efficacy of levormeloxifene in the prevention of postmenopausal bone loss and on the lipid profile compared to low dose hormone replacement therapy.

Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with levormeloxifene [1.25 (n = 51), 5, 10, or 20 mg/day], low dose continuous combined hormone replacement therapy [HRT; 1 mg 17 beta-estradiol and 0.5 mg norethisterone acetate/day], or placebo (all n = 50). All of the women were also given a daily supplement of calcium (500 mg). Serum CrossLaps decreased by about 50% in the levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more (>60%), and the placebo group (500 mg calcium alone) decreased by about 10%. The pattern was similar for bone alkaline phosphatase, except that the decreases were smaller, about 30% for the levormeloxifene groups and 50% for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in the levormeloxifene and HRT groups. Spinal bone mineral density (BMD) decreased by less than 1% in the placebo group and increased by about 2% in the levormeloxifene groups and by almost 5% in the HRT group (P < 0.001 for the difference between levormeloxifene and HRT vs. placebo). BMD of the total hip and total body changed in the same direction, although differences between groups were not as pronounced as those for BMD spine. Total cholesterol decreased by about 13--20% during levormeloxifene therapy, whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate produced a decrease of only about 8%. Levormeloxifene decreased low density lipoprotein cholesterol by about 22-30% compared with about 12% in the low dose HRT group. High density lipoprotein cholesterol was unchanged in all groups. Endometrial thickness increased both clinically and statistically significantly in the levormeloxifene groups independently of the dose; the difference from the placebo and HRT groups was significant (P < 0.001). There was no significant difference between the HRT and placebo groups. Other adverse events of interest include hot flushes, which did not occur more frequently in the levormeloxifene than the placebo groups, but occurred significantly less frequently in the HRT group (P < 0.05). Breast tenderness was much more common in the HRT group (<0.001) than in all other groups. In conclusion, the study shows that levormeloxifene, a new selective estrogen receptor modulator, has positive effects on BMD and bone turnover and apparently strong estrogenic effects on the serum concentrations of different cholesterol subfractions. Levormeloxifene at the doses tested had an estrogen-like effect on endometrium and no effect on hot flushes. The study was unable to differentiate between the effects of the different doses of levormeloxifene.

Number of years since menopause: spontaneous bone loss is dependent but response to hormone replacement therapy is independent.

In this study we examine the influence of number of years since menopause on spontaneous bone loss and response to hormone replacement therapy (HRT) in 274 women (56.1 +/- 4.2 years) completing two placebo-controlled HRT studies of 2 or 3 year duration. Both cross sectionally and longitudinally, bone loss in untreated women was greatest closest to menopause and declined thereafter (r = 0.34, p < 0.01 for lumbar spine bone loss and r = 0.25, p < 0.05 for femoral neck bone loss when correlated with number of years since menopause), such that the loss was eliminated in the femoral neck and bone mass increased in the spine in women >10 years after menopause. In contrast, bone turnover was consistently elevated throughout postmenopause, both cross-sectionally and longitudinally. The association with number of years since menopause was counteracted by both 1 and 2 mg estradiol combined with gestodene, piperazine, estrone sulfate in combination with norethisterone, and a combination of 2 mg estradiol and 1 mg norethisterone acetate. In addition, the response to various HRT regimens was independent of baseline bone mass. Whereas bone loss was significantly related to number of years since menopause, all HRT regimens applied arrested bone loss in healthy postmenopausal women, regardless of number of years since menopause.

Circadian variation in bone resorption is not related to serum cortisol.

Serum osteocalcin, serum procollagen type I carboxyterminal propeptide (sPICP), and the urinary excretion of pyridinium crosslinks (biochemical markers of bone formation and resorption) all exhibit a circadian variation with a peak during the night. This study was performed to investigate the influence of the endogenous circadian rhythm in cortisol on the biochemical markers of bone turnover. Participants included 11 patients substituted with hydrocortisone due to either hypopituitarism (n = 7) or bilateral adrenalectomy (n = 4). Their daily tablet intake of hydrocortisone was divided in four equal doses in order to abrogate the known circadian variation in cortisol. 24 healthy postmenopausal women served as controls. The study design was performed over 24 h, with blood samples taken every 3 h, and urine collected in 3 h aliquots. Urinary pyridinium crosslinks (Pyr/ Cr, D-Pyr/Cr), serum osteocalcin (sOC), and serum PICP were measured. Patients without a circadian variation in cortisol had normal circadian variation in the urinary excretion of pyridinium crosslinks and sPICP, but no circadian rhythm in serum osteocalcin. We conclude that the etiology of the circadian rhythm in the biochemical markers of bone turnover is still unknown. This study indicates that the circadian variation in sOC can be controlled by the endogenous circadian variation in serum cortisol, whereas this hormone does not control the circadian variation in either the serum PICP or the urinary excretion in pyridinium crosslinks.

Mechanism of circadian variation in bone resorption.

The diurnal variation in bone resorption markers is poorly understood and may contain essential information about regulation of bone resorption. To explore the acute regulation of bone resorption we studied bone turnover in 14 postmenopausal women during a randomized, crossover, 24 h study of oral glucose tolerance test (OGTT), normal diet, or fasting. Whereas fasting counteracted variation in bone resorption, as measured by serum C-telopeptide fragments of collagen type 1 degradation (s-CTx), OGTT and normal diet induced a 50% reduction (p < 0.001) over 2 h. For OGTT, s-CTx reverted to baseline levels after 6 h, and for normal diet s-CTx remained suppressed during the afternoon and returned to baseline overnight. Repeated OGTT at 8:00 A.M. and 8:00 P.M. in nine postmenopausal women demonstrated that identical reductions in s-CTx could be obtained at both timepoints with an intermediate return to baseline between tests. A 2 h randomized, crossover study of OGTT and fasting in 23 men and premenopausal women similarly revealed a 50% decrease in s-CTx. A randomized, crossover 2 h study of insulin tolerance test compared with fasting in six men and premenopausal women demonstrated a 20%-30% decrease in s-CTx (p < 0.01-0.05). Nine hour follow-up of ten healthy individuals during a crossover experiment of OGTT, protein, and fat intake revealed a comparable 50% reduction in s-CTx, but distinct profiles of serum glucose and serum insulin. Bone resorption was reduced by intake of food, glucose, fat, and protein and counteracted by fasting, and this seems to have been be independent of age and gender. Both exogenous and endogenous insulin stimulation tests induced a reduction in bone resorption, but this was only partial when compared with the reduction observed during food intake.

Serum CrossLaps for monitoring the response in individuals undergoing antiresorptive therapy.

The Serum CrossLaps (CTx) enzyme-linked immunosorbent assay (ELISA) is specific for a cross-linked, beta-aspartate-isomerized form of the epitope EKAHDGGR derived from the carboxyterminal telopeptide region of type I collagen alpha(1) chain. Collagen type I fragments reactive in the CTx assay are released during osteoclastic bone resorption and can be used as a measure of bone resorption activity. Our objectives were to assess the intraindividual variation of serum CTx concentration as well as the clinical value of the serum CTx assay for monitoring antiresorptive therapy in individual patients. The influence of the sampling time and fasting on the serum CTx measurements was studied with the aim of determining an optimal sampling protocol. Studies of circadian variation in serum CTx concentration in 15 postmenopausal women showed that fasting significantly reduced the average circadian variation of the marker from 36% to 8.7%. This was further supported by assessing short-term (2 weeks) intraindividual variation in ten postmenopausal women who were sampled in the morning, either fasting or nonfasting. The average short-term intraindividual coefficient of variation (CV) was 7.9% in the samples obtained from fasting women, and 14.3% in the samples obtained from nonfasting women. The long-term intraindividual biological variation was 13.4% in 44 postmenopausal women sampled every 6 months (fasting morning samples) over a 1 year period. The ability of the serum CTx assay to monitor individual responses to antiresorptive therapy was assessed in studies of the effects of hormone replacement therapy (HRT) and bisphosphonate (alendronate). Serum samples (morning fasting) were obtained from postmenopausal women treated with either bisphosphonate or HRT at baseline and then after various timepoints of therapy. Spine bone mineral density (BMD) measurements were carried out and the annual percentage change in spine BMD (alphaBMD) was calculated. Sixteen of 17 (94%) of the HRT-treated and 12 of 13 (92%) of the bisphosphonate-treated women showed a decrease in serum CTx after 6 months that was greater than the calculated least significant change (LSC) of the marker (LSC(CTx)). In contrast, only 59% of the HRT-treated and 64% of the bisphosphonate-treated women showed a response in spine BMD greater than the LSC(BMD) 0%) from women with a loss in spine BMD (alphaBMD < 0%). In conclusion, the serum CTx showed high specificity and sensitivity for monitoring individual responses to antiresorptive therapy. More than 92% of the treated women showed significant responses in serum CTx measurements after 6 months.

The relationship of natural androgens to coronary heart disease in males: a review.

Published studies dealing with the relationship between circulating levels of testosterone and dehydroepiandrosterone (sulfate) (DHEA(S)) and coronary heart disease (CHD) in males, as well as corresponding experimental animal studies are reviewed. One randomized intervention study, eight prospective and 30 cross-sectional studies have evaluated this relationship. In the intervention study, testosterone undecanoate given orally significantly improved angina pectoris in 62 patients with CHD as compared to placebo. No significant association between serum testosterone and CHD was reported in the prospective studies, whereas those studies concerning DHEAS found either no or an inverse association with CHD. Of 30 cross-sectional studies, 18 reported reduced concentrations of testosterone (primarily), and/or DHEA(S) in CHD patients as compared to normals, 11 found similar circulating levels of these androgens in controls and patients with CHD, and one study found elevated levels of DHEA(S) in patients. Animal studies (six male rabbits and one in male chicks) suggest an anti-atherogenic effect of testosterone and DHEA. In conclusion, one intervention, eight cohort and several cross-sectional studies suggest either a neutral or a favourable effect of testosterone and DHEA(S) on CHD in males.

Raloxifene and estrogen reduces progression of advanced atherosclerosis--a study in ovariectomized, cholesterol-fed rabbits.

The present study investigated the effect of raloxifene, a selective estrogen receptor modulator (SERM), on aortic atherosclerosis in 80 ovariectomized, cholesterol-fed rabbits with pre-induced atherosclerosis. The animals were fed an atherogenic diet containing 240 mg cholesterol/day for 15 weeks, after this period a baseline control group was sacrificed. Thereafter, oral treatment was initiated with either estradiol 4 mg/day (n=20), raloxifene (210 mg/day) or placebo (n=20). In the treatment period of 39 weeks, the dietary cholesterol content was reduced to 80 mg cholesterol/day. Postmortem evaluation showed a significantly increased uterine weight induced by estradiol treatment (10.3+/-1.2 g), whereas raloxifene intervention caused a decreased uterus weight (1.21+/-0.1 g) when compared to placebo (2.48+/-0.47 g). Throughout the study, serum lipids increased in all groups to levels seen in very high risk humans. After 58 weeks the cholesterol content in the aorta was 3.18+/-0.54 micromol/cm(2) (38% reduction) in the estradiol group, 3.66+/-0.52 micromol/cm(2) (29% reduction) in the raloxifene group and 5.12+/-0.60 micromol/cm(2) in the placebo group. Analyses of the aortic cholesterol content corrected for time-averaged serum cholesterol revealed that both estradiol and raloxifene therapy significantly reduced the progression of atherosclerosis (P<0.01 for both) as compared to placebo.

Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis.

CONTEXT: Treatment of osteoporosis with subcutaneous (SC) injections of rhPTH(1-34) or rhPTH(1-84) is associated with significant improvements in BMD and reductions in osteoporotic fractures. However, subcutaneous injections can be associated with discomfort and thus deteriorating compliance. OBJECTIVE: The UGL-OR1001 trial aimed to establish the efficacy and safety parameters of a novel oral tablet formulation of rhPTH(1-31)NH(2) and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis. DESIGN: 24 weeks of randomized, double-blind treatment with once daily doses of 5mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide. PATIENTS OR OTHER PARTICIPANTS: Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents. INTERVENTION(S): Orally formulated recombinant human PTH(1-31)NH(2) and placebo, or open-label subcutaneous teriparatide as a positive control. MAIN OUTCOME MEASURE(S): The primary endpoint was to characterize the percent change from baseline in bone mineral density (BMD) at L1-L4 axial lumbar spine after 24 weeks in the rhPTH(1-31)NH(2) arm. Secondary and exploratory endpoints included safety and tolerability of the oral formulation, measurement of biochemical markers of bone turnover, and evaluation of the PK profile at first and last dose. The study was registered at ClinicalTrials.gov with the identifier: NCT01321723. RESULTS: The oral tablet formulation of rhPTH(1-31)NH(2) resulted in similar PK profiles at both timepoints with mean C(max) values similar to subcutaneous administration. In the rhPTH(1-31)NH(2) arm, a 2.2% increase in lumbar spine BMD was observed compared to baseline (p<0.001), while no change was observed in the placebo arm. Open-label teriparatide resulted in a 5.1% increase in LS BMD (p<0.001). In the oral PTH study arm, the bone formation marker osteocalcin was increased by 32%, 21% and 23% at Weeks 4, 12 and 24, respectively. There was no significant increase in the level of the bone resorption marker CTx-1. CONCLUSIONS: In summary, these data demonstrate that enteric-coated oral tablet formulation technology consistently generated robust levels of exposure of rhPTH(1-31)NH(2) leading to induction of bone formation without inducing bone resorption resulting in significantly increased levels of LS BMD. Few adverse events were observed, recommending this orally delivered drug candidate for further development.

Should subchondral bone turnover be targeted when treating osteoarthritis?

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritic disease, and it is a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the entire joint, including bone and cartilage, thereby presenting alternative approaches for treatment. This review summarizes emerging observations from cell biology to preliminary clinical trials, describing interactions between the bone and cartilage components. We speculate whether a treatment for OA would be possible without targeting the bone compartment? METHODS: Peer-reviewed articles found using pre-defined search criteria and published in the PubMed database until June 2007 are summarized. In addition, abstracts from the OsteoArthritis Research Society International (OARSI) conferences in the time period 2000-2007 were included. RESULTS: Bone and cartilage health seem to be tightly associated. Ample evidence is found for bone changes during progression of OA, including, but not limited to, increased turnover in the subchondral bone, thinning of the trabecular structure, osteophytes, bone marrow lesions and sclerosis of the subchondral plate. In addition, a range of investigations has described secondary positive effects on cartilage health when bone resorption was suppressed, or deterioration of the cartilage when resorption is increased. CONCLUSION: An optimal treatment for OA might include targeting both the bone and cartilage compartments. Hence, as several cell systems are to be targeted in a safe manner, limited options seem possible.

Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se?

INTRODUCTION AND HYPOTHESIS: Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa. Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood. We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage. METHODS: This was an observational study including 1176 elderly women 60-85 years old. Women were genotyped for epsilon (epsilon) allelic variants of the ApoE gene, and data concerning serum lipids (total cholesterol, triglycerides, HDL-C, LDL-C, apoA1, ApoB, Lp(a)), hip and spine BMD, aorta calcification (AC), radiographic vertebral fracture and self-reported wrist and hip fractures, cardiovascular events together with a wide array of demographic and lifestyle characteristics were collected. RESULTS: Presence of the ApoE epsilon 4 allele had a significant impact on serum lipid profile, yet no association with spine/hip BMD or AC could be established. In multiple regression models, apoA1 was a significant independent contributor to the variation in AC. However, none of the lipid components were independent contributors to the variation in spine or hip BMD. When comparing the women with or without vertebral fractures, serum triglycerides showed significant differences. This finding was however not applicable to hip or wrist fractures. After adjustment for age, severe AC score (>or=6) and/or manifest cardiovascular disease increased the risk of hip but not vertebral or wrist fractures. CONCLUSION: The contribution of serum lipids to the modulators of BMD does not seem to be direct but rather indirect via promotion of atherosclerosis, which in turn can affect bone metabolism locally, especially when skeletal sites supplied by end-arteries are concerned. Further studies are needed to explore the genetic or environmental risk factors underlying the association of low triglyceride levels to vertebral fractures.

The influence of smoking on uterine bleeding during continuous and interrupted oral hormone therapy.

OBJECTIVE: To study the influence of smoking on uterine bleeding patterns during continuous and interrupted oral hormone therapy (HT). METHODS: Using a post-hoc strategy, we included five oral HT groups from three studies. The therapies consisted of continuous estrogen (estradiol, estradiol valerate or piperazine estrone sulfate) in combination with continuous progestogen (cyproterone acetate, gestodene or norethisterone acetate) or in combination with interrupted progestogen (norethisterone) given on days 4-6, 10-12, 16-18, 22-24 and 28-30. A total of 145 healthy postmenopausal women (54 smokers and 91 non-smokers), who had been followed for 2 years, were included in the analyses. Uterine bleeding data were collected from bleeding calendars. RESULTS: In general, smoking women experienced significantly less days with uterine bleeding per cycle than non-smoking women during continuous and interrupted HT (0.53 +/- 0.1 vs. 1.6 +/- 0.1; p < 0.001). Smoking women were also more likely than non-smoking women to be amenorrheic during these therapies (48.2% vs. 29.7%; p < 0.05). Finally, more smoking than non-smoking women attained amenorrhea during HT (94.4% vs. 76.9%p < 0.01). CONCLUSIONS: In healthy postmenopausal women, smoking may reduce uterine bleeding during interrupted and continuous HT regimens containing a broad selection of estrogens and progestogens. Further study with appropriate stratification for smoking status is warranted.

An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice.

BACKGROUND: Maintenance of the structural and functional integrity of the skeleton is a critical function of a continuous remodeling driven by highly associated processes of bone resorption and synthetic activities driven by osteoclasts and osteoblasts, respectively. Acceleration of bone turnover, accompanied with a disruption of the coupling between these cellular activities, plays an established role in the pathogenesis of metabolic bone diseases, such as osteoporosis. During the past decades, major efforts have been dedicated to the development and clinical assessment of biochemical markers that can reflect the rate of bone turnover. Numerous studies have provided evidence that serum levels or urinary excretion of these biomarkers correlate with the rate of bone loss and fracture risk, proving them as useful tools for improving identification of high-risk patients. OBJECTIVE: The aim of the present review is to give an update on biomarkers of bone turnover and give an overview of their applications in epidemiological and clinical research. DISCUSSION: Special attention is given to their utility in clinical trials testing the efficacy of drugs for the treatment of osteoporosis and how they supplement bone mass measurements. Recent evidence suggests that biochemical markers may provide information on bone age that may have indirectly relates to bone quality; the latter is receiving increasing attention. A more targeted use of biomarkers could further optimize identification of high-risk patients, the process of drug discovery, and monitoring of the efficacy of osteoporosis treatment in clinical settings.