Jordi Farrerons

Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment

Previous antiresorptive (AR) treatment may influence the response to teriparatide. We examined BMD response and safety in a subgroup of 503 postmenopausal women with osteoporosis who received teriparatide for 24 mo. Patients were divided into three groups based on their prior AR treatment: treatment‐naïve (n = 84); pretreated with no evidence of inadequate treatment response (n = 134); and pretreated showing an inadequate response to AR treatment (n = 285), which was predefined based on the occurrence of fractures, persistent low BMD, and/or significant BMD loss while on therapy. Changes in BMD from baseline were analyzed using mixed model repeated measures. Lumbar spine BMD increased significantly from baseline at 6, 12, 18, and 24 mo in all three groups. The mean gain in spine BMD over 24 mo was greater in the treatment‐naïve group (0.095 g/cm2; 13.1%) than in the AR pretreated (0.074 g/cm2; 10.2%; p < 0.005) and inadequate AR responder (0.071 g/cm2; 9.8%; p < 0.001) groups. The corresponding increases in total hip BMD were 3.8%, 2.3%, and 2.3%, respectively. Early decreases in hip BMD in the inadequate AR responder group were reversed by 18 mo of treatment. Increases in BMD between 18 and 24 mo were highly significant. Nausea (13.3%) and arthralgia (11.7%) were the most commonly reported adverse events. Asymptomatic hypercalcemia was reported in 5.0% of patients. Teriparatide treatment for 24 mo is associated with a significant increase in BMD in patients with and without previous AR use. Prior AR treatment modestly blunted the BMD response to teriparatide. Safety was consistent with current prescribing label information.

Treatment with Denosumab Reduces the Incidence of New Vertebral and Hip Fractures in Postmenopausal Women at High Risk

CONTEXT The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis. OBJECTIVE We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures. DESIGN FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial. PARTICIPANTS AND SETTING Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide. INTERVENTIONS Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU). MAIN OUTCOME MEASURES This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less. RESULTS Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture. CONCLUSIONS Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.

Monitoring Teriparatide-Associated Changes in Vertebral Microstructure by High-Resolution CT In Vivo: Results From the EUROFORS Study†

We introduce a method for microstructural analysis of vertebral trabecular bone in vivo based on HRCT. When applied to monitor teriparatide treatment, changes in structural variables exceeded and were partially independent of changes in volumetric BMD.

Sequential Treatment of Severe Postmenopausal Osteoporosis After Teriparatide: Final Results of the Randomized, Controlled European Study of Forsteo (EUROFORS)

It is unclear which treatment should be given after stopping teriparatide therapy for severe osteoporosis. In a prospective, randomized, controlled, 2‐yr study, we compared BMD effects and clinical safety of three follow‐up treatments (anabolic with teriparatide, antiresorptive with raloxifene, or no active treatment) after 1 yr of teriparatide. Postmenopausal women with osteoporosis and a recent fragility fracture received open‐label teriparatide (20 μg/d) for 12 mo before they were randomized (3:1:1) to continue teriparatide (n = 305), switch to raloxifene 60 mg/d (n = 100), or receive no active treatment for the second year (n = 102). All patients received calcium and vitamin D supplementation. Changes in areal BMD from baseline to 24 mo were analyzed using mixed‐model repeated measures. Daily teriparatide treatment for 2 yr significantly increased spine BMD by 10.7%. Patients receiving raloxifene in year 2 had no further change in spine BMD from year 1 (change from baseline, 7.9%), whereas patients receiving no active treatment had a BMD decrease of 2.5% in year 2 (change from baseline, +3.8%). At the total hip, BMD increases from baseline at 2 yr were 2.5% with teriparatide, 2.3% with raloxifene, and 0.5% with no active treatment; the respective changes at the femoral neck were 3.5%, 3.1%, and 1.3%. The study had insufficient power to assess antifracture efficacy. In conclusion, BMD increases progressively over 2 yr of teriparatide therapy in women with severe osteoporosis. After discontinuation of teriparatide, raloxifene maintains spine BMD and increases hip BMD.

Comparative Effects of Teriparatide and Strontium Ranelate on Bone Biopsies and Biochemical Markers of Bone Turnover in Postmenopausal Women With Osteoporosis

We assessed the effects on bone remodeling and histomorphometry after daily subcutaneous injections of teriparatide (n = 39, 20 μg/d) or oral strontium ranelate (SrR, n = 40, 2 g/d) in postmenopausal women with osteoporosis. Evaluable biopsies were obtained from 29 patients in the teriparatide group and 22 in the SrR group after 6 mo of treatment. The mean ± SD mineralization surfaces as a percent of bone surfaces (MS/BS, %) at the trabecular level were 7.73 ± 1.48% for teriparatide and 5.25 ± 1.15% for SrR (p = 0.219) and at the endocortical level were 17.22 ± 3.06% and 9.70 ± 2.07%, respectively (p = 0.052). Cortical porosity was 5.40 ± 0.41% in the teriparatide and 4.14 ± 0.40% in the SrR group (p = 0.037). Teriparatide induced significant increases from baseline in bone formation and resorption markers, reaching statistical significance for amino‐terminal propeptide of type I collagen (PINP) after 1 mo (+57%, p < 0.001). SrR induced small, but statistically significant, reductions from baseline in PINP at 3 (−14%, p = 0.005) and 6 mo (−19%, p < 0.001) and in serum β‐C‐terminal telopeptide of type I collagen (β‐CTX) at 1 and 3 mo (−11%, for both, p < 0.05). There were more patients with adverse events after SrR (70%) than teriparatide (41%) treatment (p = 0.013). In conclusion, the changes in biochemical markers of bone formation confirmed bone‐forming activity of teriparatide but not of SrR treatment. The effects of SrR on bone remodeling and cell activity were modest, indicating that its effects on fracture reduction may be predominantly mediated through a different mechanism than that observed with anabolic or more potent antiresorptive agents.

Persistent Body Fat Mass and Inflammatory Marker Increases after Long-Term Cure of Cushing’s Syndrome

OBJECTIVE Although increased central fat mass is characteristic of active Cushings syndrome (CS), little is known about body composition and secretion of adipokines after long-term recovery of CS. The aim of this study was to evaluate central fat mass and its correlation with adipokines and cardiovascular risk factors in patients after long-term remission of CS. METHODS Thirty-seven women with CS in remission (27 of pituitary and 10 of adrenal origin; mean age, 50 +/- 14 yr; mean time of hormonal cure, 11 +/- 6 yr) were enrolled and compared to 14 women with active CS and 85 gender-, age-, and body mass index-matched healthy controls. Total and trunk fat mass were measured by dual-energy x-ray absorptiometry scanning. Laboratory parameters and adipokine levels [including adiponectin, visfatin, soluble TNFalpha-receptor 1 (sTNF-R1), sTNF-R2, and IL-6] were measured. RESULTS Cured CS patients had more total and trunk fat mass than controls. Cured and active CS had higher levels of sTNF-R1 and IL-6 and lower adiponectin levels than controls. Higher insulin levels and blood pressure in both groups of CS patients and higher apolipoprotein B in cured CS were observed compared to controls. sTNF-R1 correlated positively with percentage of trunk fat mass and remained significant after adjusting for anthropometric parameters. CONCLUSION Despite long-term cure, patients who have suffered CS exhibit persistent accumulation of central fat, as in active hypercortisolemia, with the consequent unfavorable adipokine profile, leading to a state of low-grade inflammation. This situation determines a persistent and increased cardiovascular risk in these patients.

Utility of 99mTc‐sestamibi scintigraphy as a first‐line imaging procedure in the preoperative evaluation of hyperparathyroidism

OBJECTIVE The use of preoperative imaging in patients with hyperparathyroidism remains controversial. Many of the available techniques are insufficiently sensitive and specific to justify their routine use. We have evaluated the Sensitivity and specificity of 99mTc‐sestamibi scintigraphy in the management of patients with different forms of hyperparathyroidism.

Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing's syndrome.

Endogenous hypercortisolism and high‐dose and long‐term glucocorticoid (GC) therapy reduce bone mass. Patients in remission after successful treatment of Cushings syndrome (CS) often present hypoadrenalism and require long‐term GC replacement. The aim of our study was to evaluate whether this GC “replacement” had any further effect on bone in women after long‐term remission of CS. Thirty‐seven women (mean age: 50 ± 14 yr; 27 of pituitary and 10 of adrenal origin) with cured CS (mean time of cure: 11 ± 6 yr), 14 with active CS, and 85 sex‐, body mass index (BMI)‐, and age‐matched controls were enrolled. BMD and BMC were measured by DXA scanning. Bone biochemical markers were also measured. Duration and dose of GC replacement and duration of endogenous hypercortisolism were calculated. Cured and active CS patients had less BMC, BMD, and osteocalcin than controls (p < 0.01). These differences were observed in estrogen‐sufficient women but not in those with estrogen deficiency. Duration of GC treatment (mean: 42 mo; range, 2–420 mo) and endogenous hypercortisolism (mean: 70 mo; range, 13–241 mo) negatively correlated with BMC and lumbar spine BMD. After regression analysis, the main predictor of abnormal BMC and BMD was the duration of GC replacement (p < 0.01). Patients treated for CS persistently have less bone mass despite long‐term cure. Both duration of endogenous hypercortisolism and mainly exogenous “replacement” therapy with GC negatively affect bone mass. Thus, the additional deleterious effect of GC for the treatment of adrenal axis suppression should be considered.

A Link between Bone Mineral Density and Serum Adiponectin and Visfatin Levels in Acromegaly

CONTEXT Two adipokines highly expressed in fat mass, adiponectin with antiinflammatory and antiatherogenic properties and visfatin with an insulin-mimetic effect, are potential contributors to bone metabolism. In acromegaly, data on adiponectin are contradictory, and there are no data on visfatin. OBJECTIVES The aim of the study was to evaluate adiponectin and visfatin in acromegaly, compared to control subjects, and to analyze their relationship with body composition and bone markers. METHODS Bone markers [osteocalcin, total amino-terminal propeptide of type 1 procollagen (total P1NP), carboxy-terminal telopeptide (beta-Crosslaps)], body composition (by dual-energy x-ray absorptiometry), adiponectin (by ELISA), and visfatin (by immunoanalysis)] were evaluated in 60 acromegalic patients (24 males and 36 females) and in 105 age- and gender-matched healthy controls (33 males and 72 females). Acromegalic patients were classified as controlled, with normal IGF-I and nadir GH no greater than 1 microg/liter (n = 41), or active (n = 19). RESULTS Acromegalic patients had lower adiponectin (P < 0.01), more lean body mass (P < 0.01), more total body mass (P < 0.01), higher bone formation markers (osteocalcin and total P1NP, P < 0.05 and P < 0.01, respectively), but less bone resorption markers (beta-Crosslaps, P < 0.001) than controls. No differences in visfatin and BMD were found between patients and controls. Adiponectin correlated negatively with BMD (r = -0.374; P < 0.05) and lean mass (r = -0.301; P < 0.05) and positively with age (r = 0.341; P < 0.001) in acromegaly. Visfatin correlated negatively with BMD (r = -0.359; P < 0.05). BMD was the predictor for adiponectin and visfatin. CONCLUSIONS Acromegalic patients present hypoadiponectinemia and a favorable bone marker profile. Adiponectin and visfatin could be a link between fat mass and bone in acromegaly.

Back pain during different sequential treatment regimens of teriparatide: results from EUROFORS

Abstract Objective: To investigate changes in back pain in postmenopausal women with severe osteoporosis who received teriparatide for 24 months or switched at 12 months to raloxifene or no active treatment. Study design and methods: This prospective, controlled, randomised, open-label, 2-year study enrolled 868 postmenopausal women with osteoporosis and a recent fragility fracture. After 12 months of teriparatide (20 µg/day), 507 patients were randomised to further teriparatide (n = 305), raloxifene 60 mg/day (n = 100), or no active treatment (n = 102) for another 12 months (substudy 1); in substudy 2, 199 patients continued teriparatide. All received calcium and vitamin D supplementation. Back pain was self-assessed by patients using a visual analogue scale (0–100 mm). Changes in back pain were analysed using a mixed model for repeated measures. Results: During year 1, back pain decreased from a mean (SD) of 48.9 mm (24.0) at baseline by 11.5 mm (p < 0.001) in the total study population. In substudy 1, mean change in back pain from month 12 (randomisation) to 24 months was −2.2, −4.4 and +0.7 mm in the teriparatide (p = 0.076), raloxifene (p = 0.041), and no active treatment groups (p = 0.751). There were no between-group differences from randomization to 18 or 24 months. In a sensitivity analysis excluding patients with low baseline back pain (VAS < 30 mm), mean change from randomisation to endpoint was significant for teriparatide (−3.9 mm, p = 0.006) and raloxifene (−6.3 mm, p = 0.018) groups. Subgroup analyses of 503 patients who received teriparatide for up to 2 years showed that patients with a recent vertebral fracture had a greater decrease in back pain than those without (p < 0.05). Those with and without mild back pain (≥30 mm), and those with and without severe back pain (≥60 mm) at baseline all had a statistically significant reduction in back pain after 24 months (p < 0.05). Conclusions: Teriparatide treatment is associated with significant reductions in back pain regardless of the presence of recent vertebral fracture. These results need to be considered with caution due to the open-label design of the study.