The prospective, non-interventional PERSPECTIVES-Study examines the effectiveness of strontium ranelate (SR) in postmenopausal women with osteoporosis in relation to pain reduction and improvement of daily life abilities, frequency of falls and fracture-related treatments under practice conditions. 1147 osteoporotic patients were included and treated with 2 g SR daily. Pain, analgesics use, coping with daily life requirements, compliance and tolerability, falls and fracture treatments were analysed descriptively in 1135 patients. After three months of treatment with SR, the overall pain perception improved by 17%. The pain frequency was reduced as well, whereas the use of moderate and strong analgesics declined by 20% and 30%, respectively. The score reflecting on abilities to cope with daily life requirements improved by 14%. The incidence of serious falls, and inpatient/outpatient fracture treatments, decreased by 57% each. The physician rated the tolerability in 92.1% of the patients as very good or good. Under the daily routine practice conditions in a population including 81.6% of pre-treated patients, SR shows a rapid decrease of pain, reduced use of analgesics, improvement of daily life activities and reduction of fall incidence and fracture treatment frequency, as compared to previous therapy.

ZusammenfassungDie prospektive, nichtinterventionelle PERSPECTIVES-Studie untersucht die Wirksamkeit von Strontiumranelat (SR) bei postmenopausalen Frauen mit Osteoporose hinsichtlich der Schmerzreduktion und Alltagsbewältigung sowie der Sturzinzidenz und frakturbedingten Behandlungshäufigkeit unter Praxisbedingungen. 1147 Patientinnen wurden aufgenommen und für drei Monate mit 2 g SR/ Tag behandelt. Schmerzen, Analgetikaverbrauch, Bewältigung der Tagesaktivitäten, Compliance und Verträglichkeit, Stürze und frakturassoziierte Behandlungen wurden an 1135 Patientinnen deskriptiv analysiert. Nach drei Monaten SR-Therapie verminderte sich die Intensität des Gesamtschmerzes um 17 %. Ebenso reduzierte sich die Häufigkeit von Schmerzereignissen. Der Verbrauch von moderaten und starken Analgetika nahm um 20 % bzw. 30 % ab. Der Score hinsichtlich der Alltagsbewältigung verbesserte sich um 14 %. Schwere Stürze und frakturbedingte stationäre und ambulante Behandlungen traten insgesamt um jeweils 57 % seltener auf. Die Verträglichkeit wurde bei 92,1 % der Patientinnen durch den Arzt als sehr gut oder gut eingestuft. In einer Patientenpopulation mit 81,6 % vorbehandelten Patientinnen führt SR unter Praxisbedingungen im Vergleich zur Vortherapie zu einer schnellen Schmerzreduktion, einem reduzierten Analgetikaverbrauch, einer Verbesserung der Bewältigung des Alltags und einer Abnahme der Sturz-und frakturbedingten Behandlungshäufigkeit.

The addition of whole-body vibration to high-load resistive exercise may provide a better stimulus for the reduction of bone loss during prolonged bed rest (spaceflight simulation) than high-load resistive exercise alone.

OBJECTIVES Assessment of additive impact of alfacalcidol 1 μg daily (Alfa) on bone mineral density (BMD) and on bone strength in postmenopausal women treated with alendronate 70 mg weekly + 500 mg calcium daily. SUBJECTS AND METHODS In a randomized, double-blind, placebo controlled study, 279 postmenopausal women with osteoporosis or osteopenia participated (intention to treat analysis [ITT]; aged 73.6∓4.7 years) and were treated with 70 mg alendronate (ALN) weekly and 500 mg calcium daily for 36 months. In addition, these patients received either 1 μg alfacalcidol (Alfa) or placebo (PLC) daily. BMD was measured with Dual-Energy-X-ray-Absorptiometry (DXA) at the lumbar spine and proximal femur and at forearm and tibia with peripheral quantitative computed tomography (pQCT) at regular intervals for 36 months. RESULTS DXA-BMD of lumbar spine (L1-4) increased after 36 months, by 6.65% (p<0.0001) in the Alfa/ALN group versus 4.17% (p<0.0001) in the PLC/ALN group. Group difference was significant after 3 years (p=0.026). At the end of the study, significant differences were found in favor of the Alfa/ALN group in trabecular density (tibia) (p=0.002), cortical density (midshaft tibia) (p=0.043), and bone strength (p=0.001). The remaining parameters showed no differences between the treatment arms, apart cortical bone density at midshaft radius. CONCLUSIONS Alfacalcidol significantly increases the efficacy of alendronate treatment in osteopenic/osteoporotic postmenopausal women on spinal DXA-BMD, cortical and trabecular BMD of the tibia and also bending stiffness of the tibia.

Long-term bed-rest is used to simulate the effect of spaceflight on the human body and test different kinds of countermeasures. The 2nd Berlin BedRest Study (BBR2-2) tested the efficacy of whole-body vibration in addition to high-load resisitance exercise in preventing bone loss during bed-rest. Here we present the protocol of the study and discuss its implementation. Twenty-four male subjects underwent 60-days of six-degree head down tilt bed-rest and were randomised to an inactive control group (CTR), a high-load resistive exercise group (RE) or a high-load resistive exercise with whole-body vibration group (RVE). Subsequent to events in the course of the study (e.g. subject withdrawal), 9 subjects participated in the CTR-group, 7 in the RVE-group and 8 (7 beyond bed-rest day-30) in the RE-group. Fluid intake, urine output and axiallary temperature increased during bed-rest (p < .0001), though similarly in all groups (p > or = .17). Body weight changes differed between groups (p < .0001) with decreases in the CTR-group, marginal decreases in the RE-group and the RVE-group displaying significant decreases in body-weight beyond bed-rest day-51 only. In light of events and experiences of the current study, recommendations on various aspects of bed-rest methodology are also discussed.

Mesenchymal stem cells (MSCs) possess the capability to differentiate into bone forming cells, osteoblasts, and thus represent a new therapeutic tool in regenerative medicine. Transforming growth factor (TGF)-β is abundantly present in bone tissue where it regulates osteoblast and osteoclast functions in a complex manner. Latent TGF-β binding protein (LTBP)-1 mediates the extracellular matrix (ECM) targeting and accumulation of most TGF-β in the bone. We describe here an important regulatory role for LTBP-3 in TGF-β activation and autocrine growth control in MSCs. LTBP-3 knockdown via siRNA mediated silencing resulted in reduced cell proliferation and reduced osteogenic differentiation. When MSCs were induced to undergo differentiation, LTBP-3 levels became downregulated in parallel with reduced TGF-β activation. These changes coincided with the matrix maturation phase of osteogenic differentiation. The mechanism of LTBP-3 is most likely via TGF-β activation in the early proliferative phase of the differentiation process. Later, when TGF-β activity would inhibit further maturation and mineralization, LTBP-3 expression becomes downregulated and LTBP-1 containing large latent TGF-β1 complexes accumulate into the ECM. These complexes represent readily available targets for osteoclast mediated release and activation of TGF-β in bone tissue. Our results provide evidence that LTBP isoforms can differentially regulate TGF-β activation and ECM accumulation during osteogenic differentiation.

OBJECTIVE:To examine in a major cohort of patients whether or not musculoskeletal adverse effects (MAEs), similar to those seen in intravenous bisphosphonates (BP), might occur also in high dosage oral treatment regimens with alendronate (ALN) and risedronate (RSN).PATIENTS AND METHODS:612 consecutive patients treated in the osteoporosis outpatient clinic at Charite, Campus Benjamin Franklin, between July 2002 and October 2003 with oral ALN or RSN (mean age 68.2+/-9.7 years; 527 females, 85 males), were examined and followed up for MAEs.RESULTS:The overall frequency of any severe MAEs in our patients was low (5.6%). All severe MAEs occurred in primarily once weekly treated patients: 27 in ALN 70 mg once weekly (27/134=20.1%) and 7 in RSN 35 mg once weekly (7/28=25.0%), with no significant difference between those groups. The most frequently reported MAE was acute arthralgia in 12.6%, followed by acute back pain in 9.1% of all primarily once weekly treated cases. None of the 302 patients initially treated with daily BP reported any MAEs when later switching to once weekly administration (218 patients to ALN 70 mg once weekly and 84 patients to RSN 35 mg once weekly). With reference to recently published data, the phenomenon is probably related to dose dependent gammadelta T cell activation by accumulation of isopentenyl pyrophosphate (IPP) due to inhibition of the mevalonate pathway by nitrogen containing bisphosphonates (nBP).CONCLUSIONS:MAEs in oral BP are, in general, less common and severe than in intravenous BP. They are observed exclusively in patients starting ALN or RSN treatment with once weekly dosage regimens. In order to avoid this phenomenon, it is suggested to start ALN or RSN treatment with the lower daily dosages of ALN 10 mg daily or RSN 5 mg daily for about two weeks before switching to the overall, more convenient, once weekly dose regimen.