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.

Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term extension study.

UNLABELLED: The long-term efficacy and safety of once-monthly ibandronate were studied in this extension to the 2-year Monthly Oral Ibandronate in Ladies (MOBILE) trial. Over 5 years, lumbar spine bone mineral density (BMD) increased from baseline with monthly ibandronate 150 mg (8.4%). Long-term monthly ibandronate is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis. INTRODUCTION: Once-monthly therapy with ibandronate has been studied for up to 5 years in a long-term extension (LTE) to the 2 year MOBILE trial. METHODS: This multicenter, double-blind extension study of monthly ibandronate involved postmenopausal women who had completed 2 years of the MOBILE core study, with ≥75% adherence. Patients were reallocated, or were randomized from daily therapy, to ibandronate 100 mg monthly or 150 mg monthly for a further 3 years. RESULTS: A pooled intent-to-treat (ITT) analysis of 344 patients receiving monthly ibandronate from the core MOBILE baseline showed increases over 5 years in lumbar spine BMD (8.2% with 100 mg and 8.4% with 150 mg). Three-year data relative to MOBILE LTE baseline in the full ITT population of all 698 patients randomized or reallocated from MOBILE (including those previously on daily treatment) showed, on average, maintenance of proximal femur BMD gains achieved in the core 2-year study, with further small gains in lumbar spine BMD. In general, maintenance of efficacy was also indicated by markers of bone metabolism. CONCLUSIONS: There were no tolerability concerns or new safety signals. Monthly treatment with ibandronate 100 and 150 mg is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.

The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study.

BACKGROUND: The aim of this study was to investigate the pharmacokinetic and pharmacodynamic parameters of oral salmon calcitonin (oSCT) administered over 14 days to men and women presenting with osteoarthritis (OA). MATERIALS AND METHODS: The study was a phase-I, 2-week, placebo-controlled, double-blind, double-dummy, randomized, gender-stratified study including 73 subjects aged 57-75 years. Patients had painful OA with a Kellgren and Lawrence index score of I-III. Treatment allocations were; 0.6 mg, 0.8 mg of oSCT, or placebo. Treatment was given twice daily for 14 days. The morning dose was administered between 07:00 and 08:00 at least 30 min before breakfast. The second dose was administered 30 min before evening dinner. On treatment day 1 and 14, the morning dose was followed by 5h of fasting, and blood samples and urine were collected immediately prior to dosing and according to the protocol. Study parameters were: plasma sCT levels, bone resorption by CTX-I (serum C-terminal telopeptide of collagen type I), bone formation by osteocalcin (serum OC), and cartilage degradation by CTX-II (urine C-terminal telopeptide of collagen type II) (clinicaltrials.gov identifier: NCT00486369). RESULTS: Doses of 0.8 mg compared with 0.6 mg produced significantly higher C(max) and AUC(0-4 hrs), of calcitonin, P=0.03. This resulted in significant reductions in CTX-I and CTX-II, [P<0.0001; P=0.007]. No differences were observed between baseline and follow-up at day 14 in pharmacokinetic and pharmacodynamic parameters. Gender had no observable influence on results. CONCLUSIONS: oSCT given twice daily with a pre-dinner and morning fasting dosing resulted in reductions in markers of bone resorption and cartilage degradation.

Biochemical markers identify influences on bone and cartilage degradation in osteoarthritis--the effect of sex, Kellgren-Lawrence (KL) score, body mass index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation.

BACKGROUND: Osteoarthritis (OA) involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL) score, Body Mass Index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation. METHODS: This study was a 2-week, double-blind, double-dummy, randomized study including 37 postmenopausal women and 36 men, aged 57-75 years, with painful knee OA, and a KL-score of I - III. Subjects were allocated to one of three treatment arms: 0.6 mg or 0.8 mg oral sCT, or placebo given twice-daily for 14 days. Correlations between gender, KL score, or BMI and the bone resorption marker, serum C-terminal telopeptide of collagen type I (CTX-I), or the cartilage degradation marker, urine C-terminal telopeptide of collagen type II (CTX-II) were investigated. RESULTS: At baseline, biomarkers indicated women with OA experienced higher bone and cartilage degradation than men. CTX-I levels were significantly higher, and CTX-II levels only marginally higher, in women than in men (p = 0.04 and p = 0.06, respectively). Increasing KL score was not correlated with bone resorption, but was significantly associated with the cartilage degradation CTX-II marker in both men and women (p = 0.007). BMI was significantly and negatively correlated to the bone resorption marker CTX-I, r = -0.40 (p = 0.002), but showed only a borderline positive correlation to CTX-II, r = 0.25 (p = 0.12). Before morning treatments on days 1 and 14, no correlation was seen between CTX-I and CTX-II in either the sCT or placebo group. However, oral sCT and food intake induced a clear correlation between these bone and cartilage degradation markers. Four hours after the first sCT dose on treatment days 1 and 14, a significant correlation (r = 0.71, p < 0.001) between changes in both CTX-I and CTX-II was seen. In the placebo group a weakly significant correlation between changes in both markers was found on day 1 (r = 0.49, p = 0.02), but not on day 14. CONCLUSION: Bone resorption was higher in females than males, while cartilage degradation was correlated with increasing KL-score and only weakly associated with BMI. Bone and cartilage degradation were not correlated in untreated individuals, but dosing with oral sCT with or without food, and a mid-day meal, decreased bone and cartilage degradation and induced a correlation between both markers. Changes in bone and cartilage markers may aid in the identification of potential new treatment opportunities for OA. TRIAL REGISTRATION: Clinical trial registration number (EUDRACT2006-005532-24 & NCT00486369).

Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: Results from the ACTIVE phase 3 trial.

BACKGROUND: Abaloparatide is a 34-amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE. METHODS: Proportions of patients experiencing BMD gains from baseline of >0%, >3%, and >6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites. RESULTS: At months 6, 12, and 18, there were significantly more >3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P < 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the >0% and >6% responder thresholds. CONCLUSIONS: In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.

Investigation of the diurnal variation in bone resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin.

BACKGROUND: Bone resorption displays marked diurnal variation. Reversible inhibition of bone resorption may result in best possible efficacy when bone resorption peaks. The aim of the study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral salmon calcitonin (sCT) and the effect of timing of drug intake. METHODS: The study was a randomized, double-blind, double-dummy, placebo-controlled, phase I study to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral sCT in healthy postmenopausal women. Totally 81 subjects were included, aimed at investigation of a morning dose given at 8:00 (n = 42), a pre-dinner dose given at 17:00 (n = 20), and an evening dose given at 22:00 (n = 19). Plasma sCT concentrations and bone resorption (C-terminal-telopeptide of collagen type I (CTX-I)) was assessed. RESULTS: Morning and pre-dinner dosing led to comparable concentration of sCT of 45 pg/ml, whereas there was a tendency towards lower Cmax for the evening dosing having a mean of 24 pg/ml. The maximum difference from placebo was observed 1 to 3 hours post-dose with a 40 to 50% suppression consequent to morning dose, and about 75% suppression after pre-dinner and evening dose, due to the increase bone resorption as a result of circadian variation. CONCLUSION: The study suggests that orally administered 0.8 mg of salmon calcitonin was effective in suppression of serum CTX irrespective of time of dosing. The pre-dinner dosing resulted in optimum efficacy response corresponding to an overall suppression of bone resorption by 25%.

Bone turnover in spinal osteoporosis.

We have investigated biochemical indices of bone formation and bone resorption: serum alkaline phosphatase (sAP) plasma bone Gla protein (pBGP), fasting urinary hydroxyproline corrected for creatinine (FuHP/Cr), and fasting urinary calcium corrected for creatinine (FuCa/Cr) in 43 postmenopausal women with spinal fractures. Furthermore, histomorphometric indices of bone resorption and bone formation, as well as whole body retention (WBR) of 99m-technetium-diphosphonate (99mTc-DP), were determined. The results are compared to pre- and postmenopausal normal subjects. The results showed that indices of bone formation were mutually correlated except for sAP vs. WBR. sAP, WBR, and pBGP increased with age. sAP and WBR were not different between osteoporotics and age-matched controls, while pBGP and probably histological indices of bone formation were lower in osteoporotics than in age-matched controls. pBGP--and to a lesser extent sAP--were significantly correlated with all histological parameters reflecting bone formation. Finally, biochemical indices of bone resorption were high in osteoporotic patients and poorly correlated with histological bone resorption. The discrepancy between biochemical markers of bone formation may be related to the low sensitivity of sAP and WBR. Conversely, pBGP, sAP, and WBR may reflect different aspects of osteoblastic activity and bone mineralization. Finally, our data suggest that bone turnover increases with aging and that osteoporotic patients have higher bone resorption and probably lower bone formation than age-matched controls.

Ibandronate: a comparison of oral daily dosing versus intermittent dosing in postmenopausal osteoporosis.

The objective of this study was to compare efficacy and safety of continuous versus intermittent oral dosing of ibandronate. Two hundred forty women aged 55-75 years with postmenopausal osteoporosis were randomized to active treatment or placebo. Similar total doses of ibandronate were provided by treatment regimens with either continuous 2.5 mg of ibandronate daily (n = 81) or intermittent 20 mg of ibandronate every other day for the first 24 days, followed by 9 weeks without active drug (n = 78). The placebo group (total, n = 81) was crossed over after 12 months to receive either continuous (n = 37) or intermittent ibandronate (n = 35). By 24 months, bone mineral density (BMD) had increased significantly relative to baseline in both active treatment groups. The continuous and intermittent groups showed statistically equivalent increases in lumbar spine BMD of +5.64% (+/-0.53) and +5.54% (+/-0.53) and in total hip of +3.35% (+/-0.40) and +3.41% (+/-0.40), respectively (per protocol population). Biochemical markers of bone turnover decreased significantly in both treatment groups. The level of marker suppression was similar, although the intermittent group displayed, as expected, more fluctuation over the treatment period. The frequency of adverse events was similar in the treatment groups. In conclusion, the intermittent and continuous regimens showed equivalent changes in BMD and bone turnover. These results confirm previous preclinical findings indicating that the efficacy of ibandronate depends on the total oral dose given rather than on the dosing schedule. This supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance.

17 Beta-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women.

Forty women aged 64.7 +/- 5.1 yr with established postmenopausal osteoporosis were blindly allocated to 1 yr's treatment with either continuous combined estrogen/progestogen therapy (2 mg estradiol + 1 mg norethisterone acetate + 500 mg calcium daily) or placebo + 500 mg calcium daily. In the group treated with hormones bone mineral density in the spine (dual photon absorptiometry) and bone mineral content in the ultradistal forearm (single photon absorptiometry) increased highly significantly by 8-10% during the 1 yr of treatment. Bone mineral content in the mid-shaft of the forearm (single photon absorptiometry) and the total body bone mineral (dual photon absorptiometry) increased by 3-5% when compared to that in the placebo group, which showed virtually unchanged values at all measurement sites. Seven of the women treated with hormones were examined after a further year of treatment. BMC increased by another 3-6%, reaching a 12% increase in bone mineral density in the spine after 2 yr of treatment. Biochemical estimates of bone resorption (fasting urinary calcium and hydroxyproline) and bone formation (serum alkaline phosphatase and plasma osteocalcin), decreased significantly (P less than 0.001) in the group treated with hormones, but remained unchanged in the placebo group. The reduction in indices of bone resorption was more pronounced than that in bone formation after one year, indicating a positive bone balance. No further changes were seen in these bone turnover parameters during the second year of treatment. In the group treated with hormones, serum levels of triglycerides, total cholesterol, and low density lipoprotein cholesterol decreased by about 12% (P less than 0.05-P less than 0.01), whereas high density lipoprotein cholesterol decreased by about 8% (P less than 0.001). The high density lipoprotein cholesterol/low density lipoprotein cholesterol ratio was unchanged. The hormone treatment did not produce any major side effects, and only minor bleedings were experienced by a few women. The present study demonstrates that treatment with female sex hormones in this particular combination is a realistic approach to the treatment of women with established postmenopausal osteoporosis.

Changes in vitamin D metabolism during natural and medical menopause.

Thirty-nine women were studied longitudinally for 3 yr, during which period 10 women passed a natural menopause. Vitamin D metabolites were determined every 3 months in these 10 women. The same variables were studied in 42 premenopausal women with endometriosis treated for 6 months with nafarelin acetate (a LHRH agonist) given alone in a dose of 200 or 400 micrograms or in a dose of 400 micrograms combined with 1.2 mg norethisterone (NET)/day and followed-up for a further 6 months. No changes were seen in 1,25-dihydroxyvitamin D [1,25-(OH)2D], vitamin D-binding protein, or the free index of 1,25-(OH)2D during the natural menopause. A small increase was found in 25-hydroxyvitamin D [25OHD] and 24,25-(OH)2D3 after correction for seasonal variation. All three nafarelin groups had a significantly decreased free index of 1,25-(OH)2D, which returned to the baseline value on withdrawal of the treatment. Serum 25OHD and 24,25-(OH)2D3 were increased at 6 months and thereafter decreased to baseline values. These changes were still visible after correction for seasonal variation. Vitamin D-binding protein showed a small transient increase in the nafarelin plus NET group, but was unchanged in the other two groups. The 24-h urinary excretion of calcium increased significantly in the groups receiving nafarelin alone, whereas it remained unchanged in the nafarelin plus NET group. We conclude that detectable changes in 1,25-(OH)2D do not occur in natural menopause. Treatment with LHRH agonists produces a significant decrease in serum 1,25-(OH)2D, which does not seem to be dependent on increased bone resorption. This suggests that LHRH agonists may induce a change in other pituitary hormones involved in vitamin D regulation.

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.

Is it possible to prevent bone loss in young women treated with luteinizing hormone-releasing hormone agonists?

Recent studies have shown that treatment with the LHRH agonist nafarelin gives symptomatic and objective relief to women with endometriosis. Such a treatment, however, results in increased bone turnover and loss of bone mass. In the present study 17 women with endometriosis were treated with 400 mg nafarelin combined with 1.2 mg norethisterone (NET) for 6 months, followed by 6 months with only 1.2 mg NET. The data were compared to data from a previously published study of 9 women treated for 6 months with 400 mg nafarelin alone, followed by 6 months without treatment. In the group treated with nafarelin plus NET the biochemical parameter of bone resorption (fasting urinary hydroxyproline) remained virtually unchanged, compared to a highly significant increase in the nafarelin-treated group. Estimates of bone formation (serum alkaline phosphatase and plasma bone Gla protein) increased in the nafarelin plus NET group, but to only a minor extent compared to those in the nafarelin group. In addition, bone mineral in the forearm, the spine, and the total skeleton remained virtually unchanged in the group treated with nafarelin plus NET, compared to the bone loss of 2-6%/6 months in the nafarelin group. We conclude that addition of NET to nafarelin treatment of endometriosis seems to have a bone-sparing effect.

Applications of an enzyme immunoassay for a new marker of bone resorption (CrossLaps): follow-up on hormone replacement therapy and osteoporosis risk assessment.

An enzyme-linked immunosorbent immunoassay (ELISA) for a new marker of bone resorption (CrossLaps) was evaluated. The ELISA procedure determines degradation products of type I collagen in urine. Values obtained in the ELISA and in pyridinoline by high pressure liquid chromatography were correlated after a correction for creatinine. A high correlation was found (r = 0.77; n = 81). A group of postmenopausal women (n = 180) showed an increase of more than 70% compared to values in premenopausal women (n = 104). Hydroxyproline was increased by 23%, osteocalcin by 52%, pyridinoline by 31%, and deoxypyridinoline by 50%. A highly significant decrease (60.7%) in the CrossLaps values was seen after 12 months in samples from patients receiving hormone replacement therapy compared to a placebo group. The spontaneous bone loss in an untreated group of women was determined by repeated forearm bone mass measurement over 24 months. Baseline values obtained in the CrossLaps ELISA were correlated to the rate of loss, yielding a highly significant r value of -0.61, indicating that CrossLaps might be a useful parameter for assessment of the risk of osteoporosis in postmenopausal women.

Serum bone Gla protein: a potential marker of growth hormone (GH) deficiency and the response to GH therapy.

Serum bone Gla protein (BGP), a sensitive and specific biochemical marker of bone formation, was measured in 66 children deficient in GH before and after 3, 6, 9, and 12 months of treatment with biosynthetic human GH. Initial serum BGP levels were significantly lower than those of normal age-matched children. After 3 months of treatment, the mean serum BGP level had increased to normal. There was no relation between baseline serum BGP and the growth response, but the GH-induced increment in serum BGP levels at 3 months was highly significantly related to growth response after 12 months of therapy. The study shows that serum BGP could be a helpful biochemical marker in prediction of the growth response to long term GH therapy.

The effect of a gonadotropin-releasing hormone agonist analog (nafarelin) on bone metabolism.

The effect on bone metabolism of an agonist analog of GnRH, nafarelin, was studied in 16 premenopausal women, who received 200 micrograms nafarelin/day for 6 months, and 9 premenopausal women, who received 400 micrograms nafarelin/day for 6 months, followed by a 6-month follow-up period. Bone mineral content in the forearm (measured by single photon absorptiometry) and in the spine (measured by dual photon absorptiometry) significantly decreased after 6 months of treatment with 400 micrograms nafarelin, but 6 months after termination of treatment all bone mineral measurements had returned to pretreatment levels. The bone mineral measurements in the 200 micrograms group did not change throughout the study. In both treatment groups the biochemical estimates of bone turnover increased significantly to postmenopausal levels. Withdrawal of treatment resulted in an abrupt decrease in the bone resorption parameters (fasting urinary hydroxyproline to creatinine and calcium to creatinine excretion ratios and serum phosphate), whereas there was a protracted fall in the bone formation parameters (plasma bone Gla protein and serum alkaline phosphatase) 6 months after termination of treatment. Our findings demonstrate that nafarelin in both doses increased biochemical indices of bone turnover, that 400 micrograms/day nafarelin resulted in a significant decrease in bone mineral content, and that these effects were reversible.

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.

Effects of growth hormone (GH) on plasma bone Gla protein in GH-deficient adults.

Both deficiency and excess of GH are related to disturbances in calcium metabolism. Bone Gla protein (BGP) is the only specific marker of bone turnover identified in peripheral blood. We, therefore, determined plasma BGP in 21 adult GH-deficient patients treated with biosynthetic human GH in a double blind cross-over study. We also examined 9 patients with acromegaly before and after surgery. The GH-deficient patients had normal initial plasma BGP concentrations, whereas the acromegalic patients had highly significantly increased concentrations (P less than 0.001). During treatment with human GH, plasma BGP (and other nonspecific biochemical markers of bone turnover) increased significantly (P less than 0.001). During placebo treatment plasma BGP showed baseline values. In the acromegalic patients a significant decrease in plasma BGP concentrations was seen 1 week after surgery. The present study suggests that plasma BGP is a useful biochemical marker of the effect of treatment of both GH deficiency and GH excess/disorders.

The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-finding study.

The present article describes the results from a phase II dose finding study of the effect of ibandronate, a new, third generation bisphosphonate, in postmenopausal osteoporosis. One hundred and eighty postmenopausal, white women, at least 10 years past a natural menopause, with osteopenia defined as a bone mineral density (BMD) in the distal forearm at least 1.5 SD below the premenopausal mean, entered and 141 (78%) completed a 12 months randomized, double-blind, placebo-controlled study. The women received 0.25, 0.5, 1.0, 2.5, or 5.0 mg ibandronate daily or placebo. All women received a daily calcium supplementation of 1000 mg Ca2+. Bone mass and biochemical markers of bone turnover were measured every 3 months throughout the study period. The average changes in bone mass showed positive outcome in all regions in the groups receiving ibandronate 2.5 and 5.0 mg. The responses in the two groups were not significantly different, although there was a tendency toward a higher response in bone mass in the group receiving ibandronate 2.5 mg, where the increase in BMD was 4.6 +/- 3.1% (SD) in the spine (p < 0.001), 1.3 +/- 3.0% (SD) to 3.5 +/- 5.3% (SD) in the different regions of the proximal femur (p < 0.03 to p < 0.002), and 2.0 +/- 1.9% (SD) in total body bone mineral content (BMC) (p < 0.001). There was no significant changes in bone mass in the group receiving calcium (placebo) and ibandronate 0.25 mg. Dose-related responses were found in all biochemical markers of bone turnover. In average, serum osteocalcin decreased 13 +/- 14% (SD) (placebo) and 35 +/- 14% (SD) (5.0 mg). Urinary excretions of breakdown products of type I collagen decreased 35 +/- 21% (SD) (placebo) and 78 +/- 28% (SD) (5.0 mg), p < 0.001 in all groups. In conclusion, the results suggest that ibandronate treatment increases bone mass in all skeletal regions in a dose dependent manner with 2.5 mg being the most effective dose. Ibandronate treatment reduces bone turnover to premenopausal levels and is well tolerated.

Serum-free gamma carboxyglutamic acid (free Gla) is a poor biochemical marker of bone resorption in early postmenopausal women.

In this study, we assessed the potential value of serum-free Gla to reflect changes of bone turnover at menopause. Serum-free Gla was measured in 49 healthy postmenopausal women and 19 healthy age-matched premenopausal women. No difference in serum-free Gla concentrations was observed between the two groups. In a double-blind longitudinal study of 36 postmenopausal women (a subgroup of the above 49 women) treated with either oral oestradiol valerate in a cyclical combination with cyproterone acetate (n = 19) or placebo (n = 17) for nine months, the serum-free Gla concentration was unchanged with placebo and decreased by only 10% after hormonal replacement therapy. Initial serum-free Gla concentrations in postmenopausal women did not correlate with other biochemical markers of bone turnover. The predictive value of serum-free Gla concentration for the spontaneous rate of bone loss in early postmenopause was also assessed, and the marker showed no correlation to bone loss. These data indicate that the serum concentration of free Gla is not a useful marker of the bone turnover rate in the early postmenopause.