Change in Lumbar Spine BMD and Vertebral Fracture Risk Reduction in Teriparatide-Treated Postmenopausal Women With Osteoporosis

131

IntroductionO steoporosis is a prevalent disease that affects more than 10 million Americans. The lifetime risk of an osteoporosisrelated fracture is 50% for Caucasian women and 25% for men. Hip fractures carry a 10% to 20% increase in mortality rate within the first year after fracture. (1) The burden of the hip and other fractures can result in chronic pain, disability and other indices of reduced quality of life.Amidst these sobering statistics is the welcome advent over the past two decades of effective pharmacological therapies that reduce fracture risk. The therapies approved for the management of osteoporosis include bisphosphonates, raloxifene (a selective estrogen-receptor modulator), calcitonin, denosumab, strontium ranelate, and parathyroid hormone and PTH(1-84)]. The fulllength PTH molecule and its foreshortened amino-terminal fragment (teriparatide) are currently the only osteoanabolic agents approved for use. PTH(1-84) is not available in the United States. In November, 2002, teriparatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis and, later, in men. The approval came with restrictions in duration of therapy (18-24 months) and was limited to individuals with advanced osteoporosis at high risk for fracture. Reasons for these limitations relate, at least in part, to the unexpected occurrence of osteosarcoma and other bone neoplasms in Fischer 344 rat toxicity studies. In fact, the pivotal phase 3 trial of teriparatide was suspended when these rat toxicity data became available. The effects on rats was doseand duration-dependent, with rats being treated for approximately 80% of their lifetime and at doses three to 58 times the currently approved human dose. (2) Similar toxicity was seen for PTH(1-84) (3) Given the clear-cut efficacy data when the results of the abbreviated clinical trial results for teriparatide were analyzed, the FDA and equivalent other agencies in Europe and elsewhere granted approval of teriparatide with the stipulations that it should be used for no longer than 2 years. In the United States, the drug carries a ''black box warning'' and contraindicates its use in patients with existing risk factors for osteosarcoma, including Paget's disease of bone, prior skeletal radiation, and children with open epiphyses.Teriparatide has now been used in the United States for 10 years. With a decade of experience, it is timely to review the efficacy and safety profile of this medication. PTH(1-84) will also be reviewed. This perspective will be limited to PTH formulations that are available for the treatment of osteoporosis; we will not be discussing other anabolic agents that are currently being studied but are not yet approved, such as the sclerostin antibody (http://clinicaltrials.gov/ct2/results?term ¼ sclerostin þ anti-þ antibody). PTH mechanisms of actionTeriparatide is an amino-terminal fragment of PTH that is biologically identical to the amino-terminal fragment of human PTH. This fragment contains all the classical bio...

Section: Pth Efficacymentioning

confidence: 99%

Safety of osteoanabolic therapy: A decade of experience

Capriani

Irani

Bilezikian

2012

131

“…(28) Moreover, discrepancy exists between aBMD changes in patients treated with anti-osteoporotic pharmaceuticals and the observed reduction in fracture risk. (29)(30)(31) Thus, accurate in vivo measures of bone strength may improve diagnostics and treatment monitoring. In a study using intact cadaver forearms, the relation between observed (ie, biomechanically measured) bone strength and aBMD (correlation coefficient [R 2 ] ¼ 0.31) was inferior to that of observed bone strength and failure load predicted from FEA (R 2 ¼ 0.66), (32) demonstrating that FEA biomechanical parameters provide information on bone strength beyond aBMD.…”

Section: Discussionmentioning

confidence: 99%

Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: A one-year prospective controlled study using high-resolution peripheral quantitative computed tomography

Hansen

Hauge

Rasmussen

et al. 2012

Following parathyroidectomy (PTX), bone mineral density (BMD) increases in patients with primary hyperparathyroidism (PHPT), yet information is scarce concerning changes in bone structure and strength following normalization of parathyroid hormone levels postsurgery. In this 1-year prospective controlled study, high-resolution peripheral quantitative computed tomography (HR-pQCT) was used to evaluate changes in bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated strength in female patients with PHPT before and 1 year after PTX, compared to healthy controls. Twenty-seven women successfully treated with PTX (median age 62 years; range, 44-75 years) and 31 controls (median age 63 years; range, 40-76 years) recruited by random sampling from the general population were studied using HR-pQCT of the distal radius and tibia as well as with dual-energy X-ray absorptiometry (DXA) of the forearm, spine, and hip. The two groups were comparable with respect to age, height, weight, and menopausal status. In both radius and tibia, cortical (Ct.) vBMD and Ct. thickness increased or were maintained in patients and decreased in controls (p < 0.01). Radius cancellous bone architecture was improved in patients through increased trabecular number and decreased trabecular spacing compared with changes in controls (p < 0.05). No significant cancellous bone changes were observed in tibia. Estimated bone failure load by finite element modeling increased in patients in radius but declined in controls (p < 0.001). Similar, albeit borderline significant changes in estimated failure load were found in tibia (p ¼ 0.06). This study showed that females with PHPT had improvements in cortical bone geometry and increases in cortical and trabecular vBMD in both radius and tibia along with improvements in cancellous bone architecture and estimated strength in radius 1 year after PTX, reversing or attenuating age-related changes observed in controls. ß

“…In addition, although areal BMD measurements remain an established diagnostic tool for osteoporosis, improvement of BMD is insufficient when it comes to explaining the efficacy of an agent to reduce fracture risk. (27,28) We studied the ability of three currently available treatments, two inhibitors of bone resorption and one anabolic agent, to alter several different properties of bone strength, a prominent determinant of resistance to fracture, in 8-mo-old osteoporotic rats. Bone strength describes the greatest force, or load, which can be applied to a bone before a fracture occurs.…”

Section: Discussionmentioning

confidence: 99%

Selective Modification of Bone Quality by PTH, Pamidronate, or Raloxifene

Brennan

Rizzoli

Ammann

2009

Bone strength, a determinant of resistance to fracture, depends on BMD, geometry, microarchitecture, bone turnover rates, and properties of the bone at the material level. Despite comparable antifracture efficacy, anti-catabolics and bone anabolic agents are likely to modify the various determinants of bone strength in very different ways. Eight weeks after ovariectomy (OVX), 8-mo-old osteoporotic rats received pamidronate (APD; 0.6 mg/kg, 5 days/mo, SC), raloxifene (3 mg/kg, 5/7 days, tube feeding), PTH(1-34) (10 mg/kg, 5/7 days, SC), or vehicle for 16 wk, and we measured vertebral BMD, maximal load, stiffness and energy, microarchitecture, and material properties by nanoindentation, which allows the calculation of the elastic modulus, tissue hardness, and working energy. Markers of bone turnover, plasma osteocalcin, and urinary deoxypyridinoline (Dpd) were also determined. PTH induced greater maximal load than APD or raloxifene, as well as greater absorbed energy, BMD, and increased bone turnover markers. PTH markedly increased trabecular bone volume and connectivity to values higher than sham. Animals treated with APD had BV/TV values significantly higher than OVX but lower than sham, whereas raloxifene had no effect. Tissue hardness was identical in PTH-treated and OVX untreated controls. In contrast, APD reversed the decline in strength to levels not significantly different to sham, reduced bone turnover, and increased hardness. Raloxifene markedly increased material level cortical hardness and elastic modulus. These results show the different mechanisms by which anti-catabolics and bone anabolics reduce fracture risk. PTH influences microarchitecture, whereas bisphosphonates alter material-level bone properties, with probable opposite effects on remodeling space. Raloxifene primarily improved the material stiffness at the cortical level.