New developments in the treatment of osteoporosis.

The last 25 years have seen the development of a plethora of new, effective agents for the treatment of osteoporosis. These agents reduce the risk of spine fractures by up to 70%, hip fractures by 40-50% and non-vertebral fractures by up to 50-80%. Amino-bisphosphonates, taken orally or intravenously, remain the dominant treatment modalities for osteoporosis. These so-called anti-resorptive or anti-catabolic agents stabilize the skeleton and reduce fracture risk in osteoporotic as well as osteopenic individuals. A monoclonal antibody against receptor activator of nuclear factor κB ligand, Denosumab, constitutes a new anti-resorptive agent recently approved worldwide. In younger postmenopausal women, low-dose estrogen or estrogen/progestin still has a place for short-term (up to 5 years) preservation of bone mass, especially in women with menopausal symptoms. Likewise, selective estrogen receptor modulators should be considered in younger postmenopausal women, especially those at increased risk of breast cancer. Anabolic (bone forming) regimens, of which parathyroid hormone is the only agent currently available, aid in the build up of new bone, increase bone mass and improve bone architecture. In cancellous bone, 30-60% increases of bone mass have been documented, but cortical bone thickness also increases. These improvements lead to profound reduction in fracture rates in both the axial and appendicular skeleton. Owing to cost and the need for parenteral administration, in most countries these agents are reserved for severe osteoporosis with multiple fractures.

[Denosumab for treatment of postmenopausal osteoporosis]. / Denosumab for behandling av postmenopausal osteoporose.

BACKGROUND: Treatment with bisphosphonates reduces the risk of new fractures and is the treatment of choice for osteoporosis. Denosumab inhibits bone resorption via a different mechanism than bisphosphonates, and is a new option in the treatment of osteoporosis. In this paper we give an overview of the mode of action and clinical effects. MATERIAL AND METHODS: The paper is based on a non-systematic literature search in Pubmed/Medline. RESULTS: Denosumab is a human monoclonal antibody to receptor-activated nuclear factor kappa B (RANKL), a member of the TNF family that is formed in the osteoblast. Binding to RANKL results in reduced recruitment and activity of osteoclasts. Denosumab 60 mg given subcutaneously every six months is shown to inhibit bone resorption to a greater degree than bisphosphonates. In a three-year study of 7,868 women with postmenopausal osteoporosis, a reduction in the relative risk of vertebral, non-vertebral and hip fractures compared to placebo was found (68. 20 and 40 %, correspondingly). In the clinical trials with denosumab, the safety profile was similar to placebo, except for a slightly higher incidence of cellulitis and exanthema. Denosumab has also shown promising skeletal effects in the treatment of cancer and rheumatoid arthritis. INTERPRETATION: Treatment with denosumab has an effect on postmenopausal osteoporosis and may be an alternative to treatment with bisphosphonates. There are few adverse effects and it is simple to administer.

[Bisphosphonate treatment of osteoporosis and other skeletal diseases]. / Bisfosfonatbehandling av osteoporose og andre skjelettsykdommer.

BACKGROUND: Bisphosphonates are antiresorptive drugs widely used to treat osteoporosis. They are also used to treat hereditary skeletal diseases with systemic or local defects, and as a supplement in treatment of cancer. This paper provides an overview of pharmacokinetics, mode of action, and clinical effects. MATERIAL AND METHODS: Literature was retrieved through a non-systematic search in Pubmed/Medline. RESULTS: Bisphosphonates are derivates of pyrophosphate which bind to hydroxyapatite with high affinity. Aminobisphosphonates inhibit an enzyme in the mevalonate pathway, thereby inducing apoptosis and inhibiting osteoclast activity. A reduced incidence of vertebral and hip fractures has been shown for alendronate, risedronate and zoledronate, while ibandronate has been shown to only reduce vertebral fracture. Reduced mortality was observed in a study where patients with recent hip fracture were treated with zoledronic acid. Intravenous bisphosphonates improve compliance and are relatively simple to use. Bisphosphonates reduce the risk for skeletal complications and bone pain in breast cancer, myelomatosis and prostate cancer. They are also effective in the treatment of Paget's disease and bone marrow edema. Gastrointestinal adverse effects are relatively frequent with peroral bisphosphonates, while acute phase reactions with influenza-like symptoms are common with intravenous bisphosphonates. INTERPRETATION: Aminobisphoshonates are effective in the treatment of osteoporosis and in other bone diseases, and as an adjuvance in the treatment of cancer.

Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure.

UNLABELLED: In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained. INTRODUCTION: In the HORIZON pivotal fracture trial (PFT), enrolling 7,736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6,113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1,652). MATERIALS AND METHODS: To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for microCT analysis and histomorphometry. RESULTS: Analysis of bone structure by microCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63% median (71% mean) reduction of the activation frequency (Ac.f; p < 0.0001) and reduced mineralizing surface (MS/BS; p < 0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p < 0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid. CONCLUSIONS: Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.

The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis.

OBJECTIVES: Back pain is a major cause of suffering, disability, and cost. The risk of developing back pain was assessed following treatment with teriparatide [rh(PTH 1-34)] in postmenopausal women with osteoporosis. RESEARCH DESIGN AND METHODS: A secondary analysis of back pain findings from the global, multi-site Fracture Prevention Trial was conducted where postmenopausal women with prevalent vertebral fractures were administered teriparatide 20 microg (n = 541) or placebo (n = 544) for a median of 19 months. Treatment-emergent back pain data were collected during adverse event monitoring, and spine radiographs were obtained at baseline and study endpoint. MAIN OUTCOME MEASURES: The risk of back pain stratified by severity of new or worsening back pain and the risk of back pain associated with both number and severity of new vertebral fractures. RESULTS: Women randomized to teriparatide 20 microg had a 31% reduced relative risk of moderate or severe back pain (16.5% vs. 11.5%, P = 0.016) and a 57% reduced risk of severe back pain (5.2% vs. 2.2%, P = 0.011). Compared with placebo, teriparatide-treated patients experienced reduced relative risk of developing back pain associated with findings of: one or more new vertebral fractures by 83% (6.5% vs. 1.1%, P < 0.001), two or more new vertebral fractures by 91% (2.5% vs. 0.20%, P = 0.004), and one or more new moderate or severe vertebral fractures by 100% (5.1% vs. 0.0%, P < 0.001). CONCLUSIONS: Teriparatide-treated women had reduced risk for moderate or severe back pain, severe back pain, and back pain associated with vertebral fractures. The mechanism of the back pain reduction likely includes the reduction both in severity and number of new vertebral fractures.

Bone mineral density in females after jejunoileal bypass: a 25-year follow-up study.

BACKGROUND: Jejunoileal (JI) bypass was a widely performed operation for morbid obesity in the 1970s. The aim of this study was to investigate the long-term status of bone mineral density (BMD) after weight loss induced by this technique. SUBJECTS AND METHODS: 18 female patients (age 48-79 y, BMI 23-43 kg/m2) had BMD measurements performed 25 years after JI bypass. Dual energy x-ray absorptiometry was used, and measured sites were the lumbar spine L2-L4, left femoral neck and total hip. Vitamin and mineral supplementation had not routinely been prescribed. An assessment was made on age-adjusted BMD values, and as to whether present BMD was related to present demographic and biochemical variables. RESULTS: No significant reduction of BMD was found beyond that which was expected for age. BMD was inversely and separately related to age and body weight. The serum level of vitamin D was low in 45% of the patients, and inversely correlated to body weight and BMI. Alk phosphatase and parathyroid hormone were the best markers for low BMD. CONCLUSION: These results suggest that JI bypass has not been detrimental to bone density in females. We recommend, however, vitamin D and calcium supplements after malabsorptive procedures for morbid obesity.