The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF).

Several compounds are produced along the complex pathways of vitamin D3 metabolism, and synthetic analogs have been generated to improve kinetics and/or vitamin D receptor activation. These metabolites display different chemical properties with respect to the parental or native vitamin D3, i.e., cholecalciferol, which has been, so far, the supplement most employed in the treatment of vitamin D inadequacy. Hydrophilic properties of vitamin D3 derivatives facilitate their intestinal absorption and their manageability in the case of intoxication because of the shorter half-life. Calcidiol is a more hydrophilic compound than parental vitamin D3. Active vitamin D analogs, capable of binding the vitamin D receptor evoking vitamin D-related biological effects, are mandatorily employed in hypoparathyroidism and kidney failure with impaired 1α-hydroxylation. They have been shown to increase BMD, supposedly ameliorating calcium absorption and/or directly affecting bone cells, although their use in these conditions is jeopardized by the development of hypercalciuria and mild hypercalcemia. Further studies are needed to assess their overall safety and effectiveness in the long-term and new intermittent regimens, especially when combined with the most effective antifracture agents.

The effect of Vitamin D on falls and fractures.

Vitamin D (cholecalciferol) is important for normal development and maintenance of the skeleton. The metabolites 25(OH)D and 1,25(OH)(2)D are not only important for treating rickets and osteomalacia but also for all types and clinical stages of osteoporosis. Patients with low calcium intake and a low vitamin D status are at risk to develop secondary hyperparathyroidism, increased bone resorbtion, osteopenia and fractures. This can be counteracted by a lifelong sufficient vitamin D supply plus dietary or supplementary calcium. The effects of vitamin D on muscle, balance and cognitive functions may be an added value in fracture prevention. Today it is generally accepted that a supplementation with vitamin D and calcium should be added to every specific medical treatment of osteoporosis. In contrast to this general recommendation the potency of vitamin D alone with or without calcium to reduce the incidence of falls and/or fractures is still a debated controversy. Studies and meta-analyses during the last two decades on the effect of vitamin D and calcium supplements have not resolved the controversy on the risk of falls and fractures in healthy or osteopenic elderly populations. A thorough analysis of these trials supports our clinical experience that the efficacy of vitamin D-calcium supplementation depends on factors related to patient selection, medical intervention and study design, e.g. age, mobility, preventing falls and fractures, co-morbidity, initial vitamin D status and renal function. We conclude that plain vitamin D (cholecalciferol) with sufficient calcium intake is able to reduce the risk of falls and fractures only when adopting optimal selection criteria for patients and study conditions.

Efficacy of strontium ranelate on bone mineral density in men with osteoporosis.

In an open-label, prospective, controlled, 12-month study the effects of strontium ranelate (SR, CAS 135459-87-9) or alendronate (CAS 129318-43-0) on bone mineral density (BMD) were compared in 152 men with primary osteoporosis. Patients were randomized to SR 2 g/day (n = 76) or alendronate 70 mg/week (n = 76) supplemented daily with 1200 mg calcium and 800 IU vitamin D. The main outcome measure was percent change in lumbar spine and total hip BMD from baseline. Mean BMD (+/- SD) increased by 5.8 +/- 3.7% at the lumbar spine and 3.5 +/- 2.8% at the total hip with SR compared to increases of 4.5 +/- 3.4 % and 2.7 +/- 3.2%, respectively, with alendronate. Increases in BMD in the SR group are consistent with 1-year results from two pivotal fracture studies in postmenopausal women with osteoporosis. SR was associated with a 22% greater increase in BMD at the lumbar spine (p = 0.033) and 23% greater increase at the total hip (p = 0.002) than alendronate. New fractures were observed in 7 SR and 10 alendronate patients. Height loss (-0.1 +/- 0.7 cm) was less with SR compared with alendronate (-0.5 +/- 0.8 cm) (p = 0.026). SR was also associated with significantly greater reductions in back pain and analgesic use scores. Adverse events were experienced by 28 (37%) patients in the SR group and 38 (50%) patients in the alendronate group, none of which were serious. In men with osteoporosis, SR produced significantly greater mean increases in BMD over 12 months compared with alendronate, an agent already approved for male osteoporosis. Mean increases in BMD with SR in men were similar to those previously documented for this agent in postmenopausal women, suggesting that similar benefits on anti-fracture efficacy may be expected.

Value of a new fixed-combination pack of bisphosphonate, calcium and vitamin D in the therapy of osteoporosis: results of two quantitative patient research studies.

BACKGROUND: Osteoporotic patients with insufficient calcium intake and/or vitamin D insufficiency need adequate calcium and vitamin D supplementation with their bisphosphonate treatment. However, consistent intake and, therefore, the effectiveness of calcium/vitamin D supplementation may be impaired by several factors in the individual patient: low prescription rate or lack of advice to purchase calcium/vitamin D; reduced compliance because of the complexity of the regimen; or incorrect intake. There is a need to provide patients with a better way of taking bisphosphonate treatment with their calcium/vitamin D supplementation. To this end, a fixed-combination pack to help patients take the combination of bisphosphonate, calcium and vitamin D correctly and regularly has been developed. OBJECTIVE: To evaluate patients' understanding of administration instructions, preferences and their perceptions of compliance, convenience and completeness of a fixed-combination pack of bisphosphonate, calcium and vitamin D compared with those associated with separate packs. METHODS: The new monthly fixed-combination pack of bisphosphonate, calcium and vitamin D contains four weekly boxes. Each box contains a blister pack with one swallowable risedronate 35 mg film-coated tablet and six sachets of calcium/vitamin D effervescent granules (calcium 1000 mg and vitamin D(3) [colecalciferol] 880 IU) for dissolution in water as an oral solution, together constituting 1 week of therapy, accompanied by a patient information leaflet. Two quantitative patient research survey studies were conducted using standard questionnaires in face-to-face interviews with 400 postmenopausal women in several French cities. Participants were given the combined pack and two separate packs (risedronate 35 mg once weekly and calcium/vitamin D effervescent granules in sachets). In the first study, participants' understanding of administration instructions and preferences were evaluated. In the second study, participants' perception of compliance, convenience and completeness of the new combination pack of risedronate 35 mg plus calcium/vitamin D compared with two separate packs were evaluated. RESULTS: Participants asked about the combined pack answered a significantly higher proportion of questions about intake instructions correctly (80.3%) than participants asked about the two separate packs (70.7%) [p = 0.0004]. The combined pack was preferred by 72% of participants (p < 0.0001) for several reasons. Compared with separate packs, the combined pack was considered easier to use by 63% and easier to remember to use by 67% of participants. Participants believed that use of the combined pack would be more likely to help them take their bisphosphonate regularly (66%) and correctly (67%), and to take their calcium/vitamin D supplementation more regularly and correctly (68%), than use of separate packs. Seventy percent of participants believed that use of the combination pack would help them to not forget to take calcium/vitamin D supplementation. CONCLUSION: Use of the fixed-combination pack of risedronate 35 mg plus calcium/vitamin D once weekly could increase the likelihood that postmenopausal osteoporotic patients will receive a complete bisphosphonate, calcium and vitamin D therapy course and is likely to enhance correct intake of combination therapy. Use of this fixed-combination product will provide patients with a tool for improving adherence to recommended osteoporosis therapy and optimize the effectiveness of such treatment.

Alendronate/vitamin D3 70 mg/2800 IU with and without additional 2800 IU vitamin D3 for osteoporosis: results from the 24-week extension of a 15-week randomized, controlled trial.

Although vitamin D supplementation is a fundamental part of osteoporosis treatment, many patients do not regularly take adequate amounts. A once-weekly (OW) alendronate (ALN) preparation that includes 2800 IU of vitamin D3 in a single combination tablet (ALN+D2800) is available for treating patients and ensuring intake of vitamin D that is consistent with existing guidelines. This randomized, double-blind study extension was conducted to evaluate the safety and tolerability of ALN+D2800 and ALN+D2800 plus an additional 2800 IU vitamin D3 single tablet supplement (ALN+D5600) administered for 24 weeks in men and postmenopausal women with osteoporosis previously treated OW for 15 weeks with either ALN or ALN+D2800. The primary endpoint was the proportion of participants who developed hypercalciuria (defined as a 24-hour urine calcium >300 mg in women or >350 mg in men and an increase of >25% versus randomization baseline) at week 39. The key secondary endpoint was the proportion of participants with vitamin D insufficiency (serum 25(OH)D <15 ng/mL [37.4 nmol/L]) at the end of the study. Hypercalciuria incidence (4.2% [ALN+D5600] vs. 2.8% [ALN+D2800]), did not differ between groups (p = 0.354). No participants developed hypercalcemia. Among the participants with vitamin D insufficiency at the week 0 baseline, the prevalence of insufficiency at the end of the study was reduced by 92% in the ALN+D5600 group and by 86% in the ALN+D2800 group. The incidences of clinical adverse experiences, including drug-related adverse experiences, were similar in both groups. In subjects previously treated with ALN+D2800 for 15 weeks, the addition of 2800 IU D3 for 24 weeks did not produce hypercalcemia nor increase the risk of hypercalciuria.

Importance of calcium co-medication in bisphosphonate therapy of osteoporosis: an approach to improving correct intake and drug adherence.

BACKGROUND AND OBJECTIVE: In all of the large, pivotal, multicentre trials of bisphosphonate therapy, patients have received added calcium in amounts ranging from 500 to 1000 mg/day above individual dietary intake. Accordingly, calcium supplements or calcium/vitamin D combinations are currently recommended as co-medication with anti-resorptive therapy in all recently published guidelines on the treatment of osteoporosis. However, the consistent use or effectiveness of calcium may be impaired by several factors in the individual patient, including low prescription rate or lack of advice to purchase calcium, reduced adherence because of the complexity of the regimen, and incorrect intake (e.g. taking calcium with bisphosphonates at the same time). Patients with osteoporosis who adhere to drug therapy experience a significantly lower fracture rate. Therefore, there is a need to improve correct intake of bisphosphonates together with calcium supplementation, which may enhance adherence. The dosage regimen could be simplified by providing the two compounds in an integrated pack. Such a pack, containing one tablet of risedronic acid and six calcium carbonate tablets (Actonel), Procter & Gamble Pharmaceuticals, Weiterstadt, Germany), has been developed to facilitate correct intake. In this study, the impact of this fixed-combination pack on patient understanding of dosing instructions and on preference was tested by comparing the fixed combination with separate risedronic acid and calcium packages. PATIENTS AND METHODS: A new blister strip was developed containing one tablet of risedronic acid 35mg and six tablets of calcium carbonate 1250mg (500mg elemental calcium), representing 1 week of therapy; the control was the same medications in separate packaging. The study was conducted in a cohort of 164 postmenopausal women (mean age 69 years). Half of the participants were bisphosphonate users (n = 83). The combined understanding of five instructions - risedronic acid intake in the morning, only with water, without food, without other medication, and separate from calcium - was tested in a crossover design. Participants were also asked to state their preference for the combination packaging versus separate packs. RESULTS: Understanding of the five instructions for the separate packaging was 70%. The combination pack significantly improved understanding of these instructions to 80% (p < 0.05). Eighty-three percent of participants preferred the combination pack over separate packs (p < 0.05). The most frequently given reasons for preferring the combination pack were prefer one pack over two packs, easy/convenient to use/practical/handy, easy to understand/less confusion, and easier to remember/less likely to forget. CONCLUSIONS: The availability of a fixed-combination pack of risedronic acid 35 mg/week and calcium tablets can increase the likelihood that postmenopausal osteoporotic patients will receive both a bisphosphonate and calcium, which in turn is likely to enhance the correct intake of combination therapy.

[Drug therapy for prevention of falls and fractures]. / Medikamentöse Sturz- und Frakturprävention.

The primary goal in the practical management of osteoporosis is to prevent first or subsequent fractures and thereby to avoid acute or chronic pain and progressive skeletal deformity. Therapeutic strategies should always take the complex pathogenetic mechanisms of fractures into account, especially the fact that mechanical impacts and falls play an important role in the majority of fracture events. Accordingly, recommendations to patients and the selection of drugs should aim at both, falls and fractures. In this context there is an increasing interest in the dual effects of vitamin D on bone and muscle. Controlled studies proved that adequate vitamin D supplementation is able to improve muscle strength, coordination and body sway and thereby reduce the risk of falls and fractures. Alendronate has been studied extensively by large trials of high quality and its efficacy to reduce the risk of vertebral and nonvertebral fractures is in line with the criteria of evidence-based medicine. The innovative combination of 70 mg alendronate with 2,800 IU vitamin D in a once-weekly tablet guarantees a basic supply with this important prohormone for bone and muscle. Due to a regular combined intake an improved compliance can be anticipated which will be followed by better therapeutic results in osteoporosis patients with increased fracture risk.

Prevention and therapy of osteoporosis: the roles of plain vitamin D and alfacalcidol.

Severe vitamin D deficiency was identified only in the first decades of the last century as the most common aetiology of rickets in children and osteomalacia in adults. It was later shown that vitamin D is not, as had been supposed, the biologically active principle for healing bone disease but must be hydroxylated in the liver and then finally in the kidney to become 1alpha,25-dihydroxy-cholecalciferol, a biologically highly active renal hormone. This study reviews the various principles, mechanisms, and approaches to the treatment of different forms of osteoporosis using vitamin D, alfacalcidol, and calcitriol therapy regimens.