Comparative effects of Teriparatide and Risedronate in glucocorticoid‐induced osteoporosis in men: 18‐month results of the EuroGIOPs trial

Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18-month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE-derived strength than risedronate.

Glucocorticosteroid-induced spinal osteoporosis: scientific update on pathophysiology and treatment

Glucocorticosteroid-induced spinal osteoporosis (GIOP) is the most frequent of all secondary types of osteoporosis. The understanding of the pathophysiology of glucocorticoid (GC) induced bone loss is of crucial importance for appropriate treatment and prevention of debilitating fractures that occur predominantly in the spine. GIOP results from depressed bone formation due to lower activity and higher death rate of osteoblasts on the one hand, and from increase bone resorption due to prolonged lifespan of osteoclasts on the other. In addition, calcium/phosphate metabolism may be disturbed through GC effects on gut, kidney, parathyroid glands and gonads. Therefore, therapeutic agents aim at restoring balanced bone cell activity by directly decreasing apoptosis rate of osteoblasts (e.g., cyclical parathyroid hormone) or by increasing apoptosis rate of osteoclasts (e.g., bisphosphonates). Other therapeutical efforts aim at maintaining/restoring calcium/phosphate homeostasis: improving intestinal calcium absorption (using calcium supplementation, vitamin D and derivates) and avoiding increased urinary calcium loss (using thiazides) prevent or counteract a secondary hyperparthyroidism. Bisphosphonates, particularly the aminobisphosphonates risedronate and alendronate, have been shown to protect patients on GCs from (further) bone loss to reduce vertebral fracture risk. Calcitonin may be of interest in situation where bisphosphonates are contraindicated or not applicable and in cases where acute pain due to vertebral fracture has to be manage. The intermittent administration of 1-34-parathormone may be an appealing treatment alternative, based on its documented anabolic effects on bone resulting from the reduction of osteoblastic apoptosis. Calcium and vitamin D should be a systematic adjunctive measure to any drug treatment for GIOP. Based on currently available evidence, fluoride, androgens, estrogens (opposed or unopposed) cannot be recommended for the prevention and treatment of GIOP. However, substitution of gonadal hormones may be indicated if GC-induced hypogonadism is present and leads to clinical symptoms. Data using the SERM raloxifene to treat or prevent GIOP are lacking, as are data using the promising bone anabolic agent strontium ranelate. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.

Evaluation of 41calcium as a new approach to assess changes in bone metabolism: effect of a bisphosphonate intervention in postmenopausal women with low bone mass

A new technique was evaluated to identify changes in bone metabolism directly at high sensitivity through isotopic labeling of bone Ca. Six women with low BMD were labeled with 41Ca up to 700 days and treated for 6 mo with risedronate. Effect of treatment on bone could be identified using 41Ca after 4-8 wk in each individual. INTRODUCTION: Isotopic labeling of bone using 41Ca, a long-living radiotracer, has been proposed as an alternative approach for measuring changes in bone metabolism to overcome current limitations of available techniques. After isotopic labeling of bone, changes in urinary 41Ca excretion reflect changes in bone Ca balance. The aim of this study was to validate this new technique against established measures. Changes in bone Ca balance were induced by giving a bisphosphonate. MATERIALS AND METHODS: Six postmenopausal women with diagnosed osteopenia/osteoporosis received a single oral dose of 100 nCi 41Ca for skeleton labeling. Urinary 41Ca/40Ca isotope ratios were monitored by accelerator mass spectrometry up to 700 days after the labeling process. Subjects received 35 mg risedronate per week for 6 mo. Effect of treatment was monitored using the 41Ca signal in urine and parallel measurements of BMD by DXA and biochemical markers of bone metabolism in urine and blood. RESULTS: Positive response to treatment was confirmed by BMD measurements, which increased for spine by +3.0% (p = 0.01) but not for hip. Bone formation markers decreased by -36% for bone alkaline phosphatase (BALP; p = 0.002) and -59% for procollagen type I propeptides (PINP; p = 0.001). Urinary deoxypyridinoline (DPD) and pyridinoline (PYD) were reduced by -21% (p = 0.019) and -23% (p = 0.009), respectively, whereas serum and urinary carboxy-terminal teleopeptides (CTXs) were reduced by -60% (p = 0.001) and -57.0% (p = 0.001), respectively. Changes in urinary 41Ca excretion paralleled findings for conventional techniques. The urinary 41Ca/40Ca isotope ratio was shifted by -47 +/- 10% by the intervention. Population pharmacokinetic analysis (NONMEM) of the 41Ca data using a linear three-compartment model showed that bisphosphonate treatment reduced Ca transfer rates between the slowly exchanging compartment (bone) and the intermediate fast exchanging compartment by 56% (95% CI: 45-58%). CONCLUSIONS: Isotopic labeling of bone using 41Ca can facilitate human trials in bone research by shortening of intervention periods, lowering subject numbers, and having easier conduct of cross-over studies compared with conventional techniques.

Medical treatment of vertebral osteoporosis

Although osteoporosis is a systemic disease, vertebral fractures due to spinal bone loss are a frequent, sometimes early and often neglected complication of the disease, generally associated with considerable disability and pain. As osteoporotic vertebral fractures are an important predictor of future fracture risk, including at the hip, medical management is targeted at reducing fracture risk. A literature search for randomized, double-blind, prospective, controlled clinical studies addressing medical treatment possibilities of vertebral fractures in postmenopausal Caucasian women was performed on the leading medical databases. For each publication, the number of patients with at least one new vertebral fracture and the number of randomized patients by treatment arm was retrieved. The relative risk (RR) and the number needed to treat (NNT, i.e. the number of patients to be treated to avoid one radiological vertebral fracture over the duration of the study), together with the respective 95% confidence intervals (95%CI) were calculated for each study. Treatment of steroid-induced osteoporosis and treatment of osteoporosis in men were reviewed separately, based on the low number of publications available. Forty-five publications matched with the search criteria, allowing for analysis of 15 different substances tested regarding their anti-fracture efficacy at the vertebral level. Bisphosphonates, mainly alendronate and risedronate, were reported to have consistently reduced the risk of a vertebral fracture over up to 50 months of treatment in four (alendronate) and two (risedronate) publications. Raloxifene reduced vertebral fracture risk in one study over 36 months, which was confirmed by 48 months' follow-up data. Parathormone (PTH) showed a drastic reduction in vertebral fracture risk in early studies, while calcitonin may also be a treatment option to reduce fracture risk. For other substances published data are conflicting (calcitriol, fluoride) or insufficient to conclude about efficacy (calcium, clodronate, etidronate, hormone replacement therapy, pamidronate, strontium, tiludronate, vitamin D). The low NNTs for the leading substances (ranges: 15-64 for alendronate, 8-26 for risedronate, 23 for calcitonin and 28-31 for raloxifene) confirm that effective and efficient drug interventions for treatment and prevention of osteoporotic vertebral fractures are available. Bisphosphonates have demonstrated similar efficacy in treatment and prevention of steroid-induced and male osteoporosis as in postmenopausal osteoporosis. The selection of the appropriate drug for treatment of vertebral osteoporosis from among a bisphosphonate (alendronate or risedronate), PTH, calcitonin or raloxifene will mainly depend on the efficacy, tolerability and safety profile, together with the patient's willingness to comply with a long-term treatment. Although reduction of vertebral fracture risk is an important criterion for decision making, drugs with proven additional fracture risk reduction at all clinically relevant sites (especially at the hip) should be the preferred options.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.