Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Management of glucocorticoid-induced osteoporosis.

This review summarizes the available evidence-based data that form the basis for therapeutic intervention and covers the current status of glucocorticoid-induced osteoporosis (GIOP) management, regulatory requirements, and risk-assessment options. Glucocorticoids are known to cause bone loss and fractures, yet many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated. An European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis workshop was convened to discuss GIOP management and to provide a report by a panel of experts. An expert panel reviewed the available studies that discussed approved therapeutic agents, focusing on randomized and controlled clinical trials reporting on bone mineral density and/or fracture risk of at least 48 weeks' duration. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. The FRAX algorithm can be adjusted according to glucocorticoid dose. Available antiosteoporotic therapies such as bisphosphonates and teriparatide are efficacious in GIOP management. Several other agents approved for the treatment of postmenopausal osteoporosis may become available for GIOP. It is advised to stop antiosteoporotic treatment after glucocorticoid cessation, unless the patient remains at increased risk of fracture. Calcium and vitamin D supplementation as an osteoporosis-prevention measure is less effective than specific antiosteoporotic treatment. Fracture end-point studies and additional studies investigating specific subpopulations (pediatric, premenopausal, or elderly patients) would strengthen the evidence base and facilitate the development of intervention thresholds and treatment guidelines.

New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion.

BACKGROUND: Adequate vitamin D and calcium nutrition play a critical role in the maintenance of musculoskeletal health and are considered the first step in osteoporosis treatment. ROUNDTABLE DISCUSSION: In February 2008 Merck Sharp & Dohme sponsored a 2-day, evidence-based expert panel on the benefits of vitamin D for the patient with osteoporosis and the role of vitamin D in combination with antiresorptive therapy for the management of osteoporosis. One of the primary objectives of the meeting was to review new data on the optimal serum 25-hydroxy vitamin D [25(OH)D] levels. The symposium was attended by 29 researchers and clinicians from Europe and the Middle East. The discussion focused on optimizing vitamin D and calcium nutrition and reducing falls and fractures in osteoporotic patients. CONCLUSIONS: Current evidence and expert opinion suggests that optimal serum 25(OH)D concentrations should be at least 50 nmol/L (20 ng/mL) in all individuals. This implies a population mean close to 75 nmol/L (30 ng/mL). In order to achieve this level, vitamin D intake of at least 20 microg daily is required. There is a wider therapeutic window for vitamin D than previously believed, and doses of 800 IU per day, regardless of sun exposure, season or additional multivitamin use, appear to present little risk of toxicity. Apart from fracture and fall prevention, optimization of vitamin D status may also have additional general health benefits. Based on newly emerging data regarding calcium supplementation, and recommendations for increased vitamin D intake, the current recommendations for calcium intake in postmenopausal women may be unnecessarily high. In addition to vitamin D and calcium, treatment of patients with osteoporosis at high risk of fractures should also include pharmacologic agents with proven vertebral and non-vertebral fracture efficacy.

Diagnosis and management of osteoporosis in postmenopausal women: clinical guidelines. International Committee for Osteoporosis Clinical Guidelines.

The authors, all physicians involved in clinical research on bone and practicing clinicians, propose practical guidelines for identifying persons with osteoporosis or those at high risk of developing the disease and for managing patients who may benefit from therapy. These guidelines are based on an analysis of peer-reviewed articles published before November 1998. A flowchart of women who might benefit from treatment is provided, including clinical presentation (recent fracture of the spine, hip, or other bone or no fracture; risk factors for osteoporosis); relevant investigations (bone mineral density measurement and laboratory tests required for the differential diagnosis); and therapeutic management (general measures such as calcium and vitamin D supplementation and specific pharmacologic interventions such as estrogen, bisphosphonates, intranasal calcitonin, raloxifene, fluoride salts, and other compounds that have been assessed in randomized clinical trials). The strongest evidence for antifracture efficacy (reduction of vertebral and nonvertebral fracture risk) was observed with alendronate.

Uninterrupted oral bisphosphonate (pamidronate) therapy of patients with osteoporosis is not associated with chronic stimulation of parathyroid hormone secretion.

We have previously reported that long-term uninterrupted treatment of patients with osteoporosis with oral pamidronate is associated with increases in bone mineral content (BMC) of the lumbar spine which could not be explained by the antiresorptive action of the drug alone, raising the possibility of an additional effect of the treatment on skeletal tissue. Administration of suppressive doses of the bisphosphonate to patients with excessive osteoclastic resorption is followed by transient decreases in serum calcium and increases in parathyroid hormone (PTH) concentrations. It is possible, therefore, that chronic pamidronate therapy may stimulate PTH secretion, which in turn has been previously shown to have anabolic effects on the skeleton. To test this hypothesis we examined the changes in serum calcium. PTH and phosphate concentrations every 6 months in 33 patients with vertebral osteoporosis and no biochemical evidence of increased bone turnover, treated with oral pamidronate 150 mg daily. Serum alkaline phosphatase and urinary hydroxyproline excretion decreased significantly by 20% and 28%, respectively, after 6 months of treatment and remained at this level for the following 18 months. These changes were associated with significant increases in spinal BMC, as expected. Serum calcium, PTH and phosphate did not change from baseline values either in the whole group or when the patients were divided according to the use or not of calcium supplements. Our results exclude chronic stimulation of PTH secretion as a factor contributing to long-term increases in bone mass in patients with osteoporosis and adequate calcium intake during continuous oral pamidronate therapy.

Recovery of serum calcium concentrations following acute hypocalcemia in patients with osteoporosis on long-term oral therapy with the bisphosphonate pamidronate.

Bisphosphonates, synthetic compounds that are taken up preferentially by the skeleton and that suppress bone resorption, are currently used in the management of patients with osteoporosis. Long-term uninterrupted administration of low oral doses is the preferred mode of treatment in current clinical trials with newer bisphosphonates. These compounds have, however, a long residence time in the skeleton, and there is no information about their long-term effects on blood calcium homeostasis. We examined the effect of long-term therapy with oral bisphosphonate on blood calcium homeostasis following an acute hypocalcemic stimulus. Twenty patients with vertebral osteoporosis (10 untreated controls and 10 treated with oral pamidronate, 150 mg/day for at least 5 yr) were given intravenous infusions of sodium EDTA, and the concentrations of calcium and PTH in blood were followed for 24 h. Serum calcium concentrations decreased similarly in both groups (maximum decrease 0.21 mmol/L and 0.22 mmol/L, respectively). The recovery of serum calcium concentrations was identical in both groups, and all patients had normal concentrations at 24 h. Plasma PTH increased to a peak of 17.3 +/- 2.5 pmol/L in the control group and to 17.0 +/- 3.1 pmol/L in the pamidronate-treated patients. During the whole study period, there was no difference in either the peak PTH response or in the recovery of plasma PTH values between the two groups. However, when only PTH responses between 60 min and 24 h were examined, there were differences between the two groups. Plasma PTH values, although strictly within the normal range, were significantly higher in the pamidronate-treated patients (P = 0.001). There were no differences in the calcemic responses during this period. Further, there were no detectable changes in immunoreactive PTH-related protein in either group after the EDTA infusions. In conclusion, our study showed that longterm therapy with oral pamidronate does not affect the calcemic response to an acute hypocalcemic stimulus in patients with osteoporosis.

Quantification of adherent and nonadherent cells cultured in 96-well plates using the supravital stain neutral red.

In this study we present a rapid, simple, sensitive, inexpensive, and environment-friendly assay for determination of the number of adherent or nonadherent cells cultured in 96-well plates using the supravital stain neutral red. We describe a validation of the method and demonstrate its application to study the effects of hormones (i.e., parathyroid hormone) and cytokines (i.e., tumor necrosis factor-alpha) on the growth of primary cultures of adherent osteoblast-like cells. In addition we show that this method can also be applied to conveniently determine proliferation of cells which grow in suspension, like the CTLL-2 and B-9 cells, which are widely used to measure IL-2 and IL-6 bioactivity, respectively. In these bioassays the changes in optical density induced by IL-2 and IL-6 measured with the neutral red assay are directly comparable with the relative changes measured with the [3H]thymidine incorporation assay. For all types of cells tested, the optical density at 550 nm was directly proportional to the number of cells. The assay, which can be used for different purposes, is an excellent alternative to already existing methods. It is not only easy to perform but also very reproducible, making it ideal for screening of large numbers of samples. Therefore this assay offers a reliable and flexible tool to determine both stimulatory and inhibitory effects of hormones, cytokines, and drugs on cell growth or to study the effects on cell viability.

Palliative pamidronate treatment in patients with bone metastases from breast cancer.

PURPOSE: An open, randomized study was performed to assess the effects of supportive pamidronate treatment on morbidity from bone metastases in breast cancer patients. PATIENTS AND METHODS: Eighty-one pamidronate patients and 80 control patients were monitored for a median of 18 and 21 months, respectively, for events of skeletal morbidity and the radiologic course of metastatic bone disease. The oral pamidronate dose was 600 mg/d (high dose [HD]) during the earliest study years, then changed to 300 mg/d (low dose [LD]) because of gastrointestinal toxicity. Twenty-nine of 81 pamidronate (HD/LD) patients first received 600 mg/d and were then changed to 300 mg/d; 52 of 81 pamidronate LD patients received 300 mg/d throughout the study. Tumor treatment was unrestricted. RESULTS: An overall intent-to-treat analysis was performed. In the pamidronate group, the occurrence of hypercalcemia, severe bone pain, and symptomatic impending fractures decreased by 65%, 30%, and 50%, respectively; event-rates of systemic treatment and radiotherapy decreased by 35% (P < or = .02). The event-free period (EFP), radiologic course of disease, and survival did not improve. Subgroup analyses suggested a dose-dependent treatment effect. Compared with their controls, in pamidronate HD/LD patients, events occurred 60% to 90% less frequently (P < or = .03) and the EFP was prolonged (P = .002). In pamidronate LD patients, event-rates decreased by 15% to 45% (P < or = .04). Gastrointestinal toxicity of pamidronate caused a 23% drop-out rate, but other cancer-associated factors seemed to contribute to this toxicity. CONCLUSION: Pamidronate treatment of breast cancer patients efficaciously reduced skeletal morbidity. The effect appeared to be dose-dependent. Further research on dose and mode of treatment is mandatory.

Maintained improvement in calcium balance and bone mineral content in patients with osteoporosis treated with the bisphosphonate APD.

The effects of the (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in osteoporosis were investigated in a series of open studies. Seven patients received a high dose of 600 mg/day of APD orally and showed an increase in calcium balance of 5.5 mmol/day (P less than 0.01) within a period of 10 days. In a group of 14 patients with osteoporosis, receiving a low dose of 150 mg/day of APD continuously, the mean calcium balance rose from -0.72 +/- 0.59 mmol/day before treatment to 1.33 +/- 0.87 mmol/day (P less than 0.005) after 1 year. In 24 patients treated with APD 150 mg/day for a mean period of 3.7 years (range 1.4-6.2) repeated dual photon absorptiometry measurements of the lumbar spine showed a mean rate of increase in bone mineral content of 3.1 +/- 1.0% per year (P less than 0.005). This yearly gain in bone mineral content appeared continuous for several years of treatment. In a comparable group of 19 patients with osteoporosis who also received conventional care and treatment but no APD, no significant changes in bone mineral content were found. Addition of a low dose of APD to conventional treatment of osteoporosis does not only prevent bone loss but induces a continuous gain in bone mass. These results justify long-term prospective studies with uninterrupted low dose APD treatment in osteoporosis.

Long-term experience of alfacalcidol in renal osteodystrophy.

Thirteen patients receiving regular haemodialysis, with biochemical or radiological evidence of renal osteodystrophy, were treated with alfacalcidol (1 alpha hydroxy vitamin D3) for four years. During the first eighteen months of treatment plasma alkaline phosphatase and serum parathyroid hormone concentrations fell and subperiosteal phalangeal erosions improved. Thereafter plasma alkaline phosphatase and serum parathyroid hormone concentrations rose and after four years' treatment only four patients had a normal plasma alkaline phosphatase, only five a normal serum parathyroid hormone level and in only six had the erosions healed completely. Hypercalcaemia occurred in twelve patients, plasma calcium exceeding 3.0 mmol/l in ten. Plasma calcium rose abruptly close to the time when plasma alkaline phosphatase became normal and often remained raised despite reduction in dosage of alfacalcidol. We have reservations about the ultimate value of long-term treatment with alfacalcidol in haemodialysed patients with renal osteodystrophy and urge caution in its use.

End-organ resistance to 1,25-dihydroxycholecalciferol.

A 13-year-old girl with total alopecia who in infancy had rickets unresponsive to large doses of vitamin D2 is described. She had profound hypocalcaemia which was resistant to treatment with high doses of dihydrotachysterol, 1 alpha-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol. Serum concentrations of 25-hydroxyvitamin D were normal but those of 1,25-dihydroxycholecalciferol were markedly raised (674 and 745 pg/ml). In addition, 24,25-dihydroxyvitamin D was undetectable in serum. Administration of synthetic 24,25-dihydroxycholecalciferol was followed by normocalcaemia which persisted long after treatment was stopped. Her sister, who died at the age of 10 months, also had had total alopecia, rickets, and hypocalcaemia resistant to vitamin-D2 therapy. In this familial syndrome there seems to be end-organ resistance to the action of 1,25-dihydroxycholecalciferol, possibly as a result of changes at the receptor sites.

1alpha-hydroxyvitamin D3 in the long-term management of hypoparathyroidism and pseudohypoparathyroidism.

Normocalcaemia was restored and maintained in eleven hypoparathyroid and two pseudohypoparathyroid patients treated for up to 36 months with 1alpha-hydroxyvitamin D3. It was found to be a potent compound, maintenance doses ranging from 4 microgram weekly to 2 microgram daily. Supplementary oral calcium was used in acutely and profoundly hypocalcaemic patients but was given to only two patients as part of long-term therapy. Hypercalcaemic episodes occurring during treatment were of short duration and could be controlled by withdrawal of medication alone.

1-alpha-hydroxycholecalciferol for renal osteodystrophy.

Fourteen patients with renal osteodystrophy were treated for at least one year with 1-alpha-hydroxycholecalciferol (1-alpha-OHD3) in a dose varying from 1 microgram/week to 3 microgram/day. Plasma calcium and inorganic phosphorus concentrations increased significantly. The plasma alkaline phosphatase concentration fell in 11 of the 12 patients in whom it was initially raised and returned to normal in seven. Serum parathyroid hormone concentrations were initially raised in all patients, but they decreased significantly with treatment and became normal in eight patients within one year. The 10 patients with radiological abnormalities showed some improvement. Hypercalcaemia occurred in 11 patients, and necessitated a reduction in the dose of 1-alpha-OHD3 in some. 1-alpha-OHD3 was effective in reducing the biochemical and radiological abnormalities of renal osteodystrophy, but it should be used wtih care, and plasma calcium concentrations should be monitored.