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.

[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.

[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.

Effect of regional fat loss assessed by DXA on insulin resistance and dyslipidaemia in obese women.

OBJECTIVE: To investigate the impact of reduction in total fat mass (FM) and regional FMs on indices of insulin resistance and dyslipidaemia in obese women (BMI > 30 kg/m(2)) after a 1-year weight loss (WL) program; and, secondly, to investigate the potential predictive effect of baseline insulin resistance on reduction in total and regional FMs. MATERIAL AND METHODS: In 35 women with > 4 kg weight loss, body composition by DXA (dual X-ray absorptiometry), fasting insulin, C-Peptide, insulin resistance (HOMA-IR), insulin sensitivity (QUICKI), metabolic clearance rate (MCRestOGTT) and serum lipids were assessed. RESULTS: Mean WL was 9.6%; trunk and leg FM were reduced proportionally (14.9-14.7%). Improvement in HOMA-IR was 34.7%, insulin 30.7%, QUICKI 8.6% and MCRest OGTT 74%. The reduction in total, trunk and leg FM were similarly correlated with improvement in indices of insulin resistance (p < 0.001-0.05) and also with initial HOMA-IR (p = 0.000-0.02). In linear regressions improvement in HOMA-IR was similarly related with these FMs (p = 0.008), and initial HOMA predicted loss of trunk FM (p = 0.01). In multivariate analysis improvement in HOMA-IR was explained by loss of total FM (R(2) = 0.20, p = 0.004); improvement of QUICKI by loss of leg FM (R(2) = 0.33, p < 0.001). CONCLUSION: Loss of leg FM and trunk FM had similar importance for the improvement in insulin resistance. Baseline HOMA-IR predicted the potential for reduction in trunk FM.

Effect of loss of regional fat assessed by DXA on insulin resistance and dyslipidaemia in obese men.

OBJECTIVE: To investigate the impact of reduction in total fat mass (FM) and regional FMs on indices of insulin resistance and dyslipidaemia in obese men (BMI > 30 kg/m²) after a 1-year weight loss (WL), and secondly, to examine the potential predictive effect of baseline insulin resistance on reduction in total and regional FMs. MATERIAL AND METHODS: In nine men with WL > 4 kg, body composition by DXA (dual X-ray absorptiometry) and indices of insulin resistance were assessed: fasting insulin, C-Peptide and HOMA-IR. Insulin sensitivity (QUICKI) and serum lipids were also assessed. RESULTS: Mean WL was 10.8%; Δ trunk and Δ leg FM were reduced by 30.1% and 21.3%, respectively, increasing leg/trunk FM ratio by 13.2%. Improvement in HOMA-IR was 63.1%, insulin 59.1%, and in QUICKI 17.4%. Loss of total FM, trunk FM, and increase in leg/trunk FM ratio were correlated with improvement in HOMA-IR (p < 0.001-0.05). Linear regression analysis of ln-transformed improvements in HOMA-IR was non-significantly related with losses of trunk FM and increases in leg/trunk FM ratio (p = 0.06). Multivariate analysis suggested improvements in fasting insulin and C-Peptide could be explained by leg/trunk FM ratio (R² = 0.60, p = 0.013, R² = 0.37, p = 0.012, respectively) and in HOMA-IR by trunk FM (R² = 0.42, p = 0.06). The loss of FM and change in FM distribution had no effect on serum lipids. CONCLUSION: Both loss of trunk FM and increase in leg/trunk FM ratio assessed by DXA contribute to the improvement in insulin resistance.

Insulin resistance and dyslipidaemia in obese premenopausal and postmenopausal women matched for leg/trunk fat mass ratio.

OBJECTIVES: To investigate the influence of age, menopausal stage and selected hormonal factors on insulin resistance and dyslipidaemia in obese (BMI>30 kg/m(2)) pre- and postmenopausal women. MATERIAL AND METHODS: Thirty- eight pre- and postmenopausal women were matched one by one for leg/trunk fat mass (FM) ratio. Body composition and regional FM by dual X- ray absorptiometry (DXA), fasting glucose, insulin and C- peptide, insulin resistance by homeostasis model assessment (HOMA- IR), insulin sensitivity by quantitative insulin sensitivity check index (QUICKI) and metabolic clearance rate (MCRestOGTT), insulin secretion (HOMAsecr), serum lipids, oestradiol, SHBG, testosterone and testosterone index (total testosterone/SHBG), free thyroxine, free triiodothyronine, cortisol and IGF- 1 were assessed. RESULTS: HDL- cholesterol was higher (p=0.025) and total cholesterol/HDL- cholesterol ratio lower (p=0.026) in post- than in premenopausal women. No differences in parameters of insulin resistance or hormonal factors except oestradiol were found. In forward stepwise multiple regression analysis, cholesterol/HDL- cholesterol ratio was negatively predicted by age (R(2)=0.25, p=0.02) and HDL- cholesterol negatively (R(2)=0.16, p=0.013) predicted by belonging to the premenopausal group. MCRestOGTT was unfavourably predicted by IGF- 1 (R(2)=0.28, p=0.005) and testosterone (R(2)=0.36, p=0.048). Because of the relatively small number of subjects studied, interpretation of the results may to some extent have limited general validity. CONCLUSION: FM distribution is the major determinant of insulin resistance and dyslipidaemia, with only minor roles for menopausal status, age as such and age- related changes in hormonal factors in the regulation of glucose and lipid metabolism.

Leg fat mass as measured by dual X-ray absorptiometry (DXA) impacts insulin resistance differently in obese women versus men.

OBJECTIVE: To investigate the association between regional fat mass (FM) and insulin resistance and dyslipidaemia in obese women and men. MATERIAL AND METHODS: Body composition was measured by dual-energy X-ray absorptiometry (DXA) in 109 obese women and 113 obese men. Insulin resistance was measured by (HOMA-IR); insulin sensitivity was estimated by metabolic clearance rate (MCRestOGTT) and insulin secretion by HOMAsecr. Serum lipids were assessed. RESULTS: In women, leg FM was negatively (favourably) associated with HOMA-IR and cholesterol/HDL-cholesterol ratio (p<0.05). Trunk FM was positively (unfavourably) associated with HOMA-IR. Leg/trunk FM ratio was negatively associated with HOMA-IR (p<0.001), cholesterol/HDL-cholesterol ratio (p<0.001) and triglycerides (p<0.01); positively (favourably) with MCRestOGTT (p<0.01) and HDL-cholesterol (p<0.05). No associations were found in men. In women, multiple regression analysis demonstrated that leg/trunk FM ratio was the only explanatory FM for HOMA-IR and MCRestOGTT (R(2) = 0.23 and R(2) = 0.13, respectively; p<0.001), but postmenopausal status was also of importance (R(2) = 0.23, p = 0.019 and R(2) = 0.29, p = 0.015, respectively). CONCLUSIONS: Leg FM has a favourable influence on insulin resistance and dyslipidaemia in obese women, but not demonstrated in this cohort of obese men.

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.

Impact of lean mass and fat mass on bone mineral density: The Hordaland Health Study.

OBJECTIVES: To examine the relationship between soft tissue composition and bone mineral density (BMD) of the hip and whether these relationships differ by gender and age. METHODS: Femoral neck BMD and total body soft tissue composition were measured by dual X-ray absorptiometry in a population-based sample of 5205 men and women 47-50 and 71-75 years old. Analysis of covariance was used to explore possible modifying effects of sex and gender on the impact of fat and lean mass on BMD. RESULTS: The difference in BMD per kilo lean mass (LM) was larger than the difference per kilo fat mass (FM). The effect of FM on BMD was significantly greater among women than among men. In multivariate adjusted analyses, 10kg increase in LM was associated with a 0.083 (95% confidence interval [CI]: 0.075, 0.092)g/cm(2) increase in BMD. A 10kg increase in FM was associated with 0.013 (0.007, 0.019)g/cm(2) increase in BMD among men and 0.021 (0.017, 0.026)g/cm(2) among women. There was indication of a steeper dose-response relationship at lower levels of FM among women. CONCLUSIONS: Compared to FM, LM was generally more strongly related to BMD of the femoral neck in middle-aged and elderly men and women. FM was a significantly stronger predictor of BMD among women than among men, particularly at lower levels of FM.

[Treatment of osteoporosis with parathyroid hormone]. / Behandling av osteoporose med parathyreoideahormon.

BACKGROUND: Until recently, antiresorptive therapy has been the only treatment of osteoporosis. Parathyroid hormone (PTH) represents a new treatment principle. PTH given intermittently stimulates the osteoblasts and bone formation. We here present the effect of PTH on bone metabolism, bone mineral density and fracture reduction, and discuss the role of PTH in osteoporosis treatment. MATERIAL AND METHODS: The article is based on literature retrieved from Pubmed/Medline and on own experience from participation in multicentre studies. RESULTS AND INTERPRETATION: Treatment with PTH stimulates bone formation and causes a more pronounced increase in bone mineral density than bisphosphonates and results in a significant reduction of vertebral and nonvertebral fractures. The treatment is very expensive, and is therefore used and reimbursed restrictively.

Effects of risedronate 5 mg/d on bone mineral density and bone turnover markers in late-postmenopausal women with osteopenia: a multinational, 24-month, randomized, double-blind, placebo-controlled, parallel-group, phase III trial.

BACKGROUND: Randomized clinical trials have shown that risedronate reduces the risk for both ver- tebral and nonvertebral fractures in postmenopausal women with osteoporosis (bone mineral density [BMD] T-score, <-2.5). If left untreated, osteopenia (T-score, between -1 and -2.5) may progress to osteo- porosis. Risedronate sodium, a pyridinyl bisphospho- nate, is an antiresorptive drug approved by the US Food and Drug Administration for the prevention and treatment of osteoporosis in postmenopausal women. Although the effects of risedronate in preventing frac- tures has been established, its effects in maintaining or increasing BMD in osteopenia have not. OBJECTIVE: In this clinical trial, the efficacy and tol- erability of risedronate in improving and maintaining BMD levels in late-postmenopausal women with os- teopenia were assessed. METHODS: This 24-month, randomized, double- blind, placebo-controlled, parallel-group, Phase III trial was conducted at 14 study centers across Finland, The Netherlands, Norway, Spain, and Sweden. Late- postmenopausal (> or =5 years from menopause) women with lumbar spine (LS) BMD T-score between -1 and -2.5 and the presence of > or =1 additional risk factor for osteo- porosis or proximal femur (Fern) BMD T-score < or = -1 were randomized to receive risedronate 5 mg (n = 114) or placebo (n = 57) PO QD for 24 months. The primary efficacy end point was the percentage change from baseline in LS BMD at study end point (24 months or last observation carried forward). Secondary efficacy end points were the percentage changes from base- line in total proximal Fern BMD and 2 bone turnover markers-urinary type I collagen cross-linked N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBAP)-at 12 months and study end point. Tolerability was assessed using reported adverse events (AEs), laboratory analysis, and physical exami- nation including vital-sign measurements. RESULTS: A total of 171 women were included (mean [SD] age, 65.9 [6.8] years; mean [SD] LS BMD T-score,-1.82 [0.42]; risedronate group, 114 patients; placebo group, 57). At study end point, LS BMD had significantly increased from baseline in the risedronate group (P < 0.05) but remained unchanged in the placebo group (mean [SE] %Delta, +4.49% [0.38%] and +0.05% [0.54%], respectively; P < 0.001). Between- treatment differences in mean (SE) percentage changes from baseline in LS BMD and Fem BMD were signif- icant at 12 months and study end point (LS BMD, both P < 0.001; Fem BMD, P = 0.002 and P < 0.001, respectively). At 12 months and study end point, ris- edronate use was associated with significantly reduced concentrations of uNTx and sBAP compared with placebo (both, P < 0.001). Risedronate treatment was well tolerated with regard to gastrointestinal AEs; the most frequent AEs in the risedronate group were hy- pertension (n = 13), constipation (n = 8), and hyper- cholesterolemia (n = 8). CONCLUSIONS: In these late-postmenopausal women with LS osteopenia and > or=1 additional risk factor or hip osteopenia, 24-month treatment with risedronate 5 mg/d was associated with the prevention of bone loss at the spine and hip (based on significant increases in BMD in the LS and total proximal Fem) and reduced bone resorption (based on significantly reduced concen- trations of uNTx and sBAP) and was well tolerated.

Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment.

UNLABELLED: A follow-up in 1262 women was conducted after the discontinuation of teriparatide. The hazard ratio for combined teriparatide group (20 and 40 microg) for the 50-month period after baseline was 0.57 (p = 0.002), suggesting a sustained effect in reducing the risk of nonvertebral fragility fracture. INTRODUCTION: Treatment with teriparatide [rhPTH(1-34)] 20 and 40 microg once-daily subcutaneous dosing significantly reduced the risk of nonvertebral fragility fractures over a median exposure of 19 months. MATERIALS AND METHODS: All participants in the Fracture Prevention Trial were invited to participate in a follow-up study. Prior treatment assignments were revealed, and patients were able to receive osteoporosis treatments without restriction. RESULTS: Approximately 60% of the 1262 patients received an osteoporosis treatment at some time during follow-up, with greater use in the former placebo group than in the combined former teriparatide group (p < 0.05). The hazard ratios for nonvertebral fragility fractures in each teriparatide group relative to placebo were statistically significant for the 50-month period including treatment and follow-up (p < 0.03). In the follow-up period, the hazard ratio was significantly different between the 40 mug and combined groups versus placebo but not for the 20 microg group versus placebo. However, the 20 and 40 microg groups were not different from each other. Kaplan-Meier analysis of time to fracture showed that the fracture incidence in the former placebo and teriparatide groups diverged during the 50-month period including teriparatide treatment and follow-up (p = 0.009). Total hip and femoral neck BMD decreased in teriparatide-treated patients who had no follow-up treatment; BMD remained stable or further increased in patients who received a bisphosphonate after teriparatide treatment. CONCLUSIONS: While the study design is observational, the results support a sustained effect of teriparatide in reducing the risk of nonvertebral fragility fractures up to 30 months after discontinuation of treatment.

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.

Vertebral deformities in rheumatoid arthritis: a comparison with population-based controls.

BACKGROUND: Previous studies have shown an increased prevalence of osteoporosis in rheumatoid arthritis (RA), but the extent of osteoporotic fractures is not clarified. The aim of this study was to compare the prevalence of vertebral deformities in a representative, population-based cohort of female patients with RA with that in matched controls, and to examine the relationship between deformities and RA, bone mineral density (BMD), and corticosteroid use. METHODS: Female patients (mean age, 63.0 years; range, 50.7-73.6 years) were recruited from a county register of patients with RA. Population controls were matched for age, sex, and residential area. Participants had thoracolumbar radiographs taken according to a standardized procedure, and BMD was measured at the hip and spine (L2-L4). RESULTS: The overall number of vertebral deformities was substantially higher in the RA group compared with controls (147 vs 51, applying the morphometric criteria), with a highly significant difference between patients and controls regarding the presence of multiple deformities measured morphometrically (11.2% vs 4.8%; odds ratio, 2.60; 95% confidence interval, 1.21-6.04) and moderate or severe deformities measured semiquantitatively (17.3% vs 10.0%; odds ratio, 2.00; 95% confidence interval, 1.11-3.74). In Poisson regression analysis, vertebral deformities were independently associated with RA, BMD, and long-term corticosteroid use. CONCLUSIONS: Vertebral deformities are markedly increased in patients with RA compared with controls, especially regarding severe and multiple deformities. A diagnosis of RA was associated with vertebral deformities independently of BMD and long-term corticosteroid use. These findings have important implications for prevention of established osteoporosis in RA.