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Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The diagnosis of osteoporosis centres on the assessment of bone mineral density (BMD). Osteoporosis is defined as a BMD 2.5 SD or more below the average value for premenopausal women (T score < -2.5 SD). Severe osteoporosis denotes osteoporosis in the presence of one or more fragility fractures. The same absolute value for BMD used in women can be used in men. The recommended site for diagnosis is the proximal femur with dual energy X-ray absorptiometry (DXA). Other sites and validated techniques, however, can be used for fracture prediction. Although hip fracture prediction with BMD alone is at least as good as blood pressure readings to predict stroke, the predictive value of BMD can be enhanced by use of other factors, such as biochemical indices of bone resorption and clinical risk factors. Clinical risk factors that contribute to fracture risk independently of BMD include age, previous fragility fracture, premature menopause, a family history of hip fracture, and the use of oral corticosteroids. In the absence of validated population screening strategies, a case finding strategy is recommended based on the finding of risk factors. Treatment should be considered in individuals subsequently shown to have a high fracture risk. Because of the many techniques available for fracture risk assessment, the 10-year probability of fracture is the desirable measurement to determine intervention thresholds. Many treatments can be provided cost-effectively to men and women if hip fracture probability over 10 years ranges from 2% to 10% dependent on age.

There is no one cause of bone fragility; genetic and environmental factors play a part in development of smaller bones, fewer or thinner trabeculae, and thin cortices, all of which result in low peak bone density. Material and structural strength is maintained in early adulthood by remodelling; the focal replacement of old with new bone. However, as age advances less new bone is formed than resorbed in each site remodelled, producing bone loss and structural damage. In women, menopause-related oestrogen deficiency increases remodelling, and at each remodelled site more bone is resorbed and less is formed, accelerating bone loss and causing trabecular thinning and disconnection, cortical thinning and porosity. There is no equivalent midlife event in men, though reduced bone formation and subsequent trabecular and cortical thinning do result in bone loss. Hypogonadism contributes to bone loss in 20-30% of elderly men, and in both sexes hyperparathyroidism secondary to calcium malabsorption increases remodelling, worsening the cortical thinning and porosity and predisposing to hip fractures. Concurrent bone formation on the outer (periosteal) cortical bone surface during ageing partly compensates for bone loss and is greater in men than in women, so internal bone loss is better offset in men. More women than men sustain fractures because their smaller skeleton incurs greater architectural damage and adapts less effectively by periosteal bone formation. The structural basis of bone fragility is determined before birth, takes root during growth, and gains full expression during ageing in both sexes.

Background: Osteoporosis and related fractures are a major complication after organ transplantation. The aim of this study was to find out the frequency and predictors of osteoporotic fractures after cardiac or liver transplantation., Methods: 235 consecutive patients who had a cardiac transplant (n=105; 88 men, 17 women) or a liver transplant (130; 75 men, 55 women) were followed. Vertebral fractures were assessed by a standardised analysis of spinal radiographs before and annually after transplantation. Clinical and non-vertebral fracture data were noted from hospital records., Findings: In the first and second years after transplantation, the proportion of patients (Kaplan-Meier estimates) who had at least one vertebral fracture was slightly higher in the cardiac group (first year 21%, second year 27%) than in the liver group (first year 14%, second year 21%). In the third and fourth years, one third of patients from both groups had had one or more vertebral fractures. Non-vertebral fractures occurred in nine patients (7%) after liver transplantation and avascular necrosis of the hip head in three patients (3%) after cardiac transplantation. In both groups, no dose-dependent effect of immunosuppressive therapy on fracture development could be identified. Independent predictors assessed by multivariate analysis were age (hazard ratio [95% CI] increase of 5 years, 1.71 [1.1-2.7]) and lumbar bone-mineral density (decrease of 1 SD t score, 1.97 [1.2-3.2]) in cardiac transplantation patients, and vertebral fractures before transplantation (6.07 [1.7-21.7]) in the liver group., Interpretation: The high frequency of osteoporotic fractures in the 2 years after transplantation and the limitations of reliable fracture-risk predictions, show the need to investigate preventive therapies.

Generalised osteoporosis is a feature of established rheumatoid arthritis but whether this is a consequence of treatment, immobility, or disease activity has been unclear. We estimated bone mineral density by dual energy x-ray absorptiometry on 148 patients with early rheumatoid arthritis before treatment with corticosteroids or disease-modifying drugs and 730 normal controls. Scans were done at 12-month intervals in patients and at 0 and 12 months on 50 of the controls matched for menopausal status. At presentation, bone mineral density of patients did not differ from controls. However, patients with disease for less than 6 months had significantly higher spinal bone mineral density than those of longer duration. Over the next 12 months, bone mineral density loss was greater in patients with rheumatoid arthritis compared with controls; significantly so for early disease (eg, -2.4 [0.8] vs -0.6 [0.4] g/cm2, p < 0.05 in the spine and -4.3 [0.8] vs -0.4 [0.5] g/cm2, p < 0.001 in the trochanter). For the lumbar spine, only disease activity was significantly associated with this bone mineral density loss. For patients with active disease over 2 years, mean bone mineral density loss at each site was between 5.5 and 10% (p < 0.01 compared to patients with inactive disease). Suppression of disease activity stabilised this bone loss. In patients with rheumatoid arthritis significant amounts of generalised skeletal bone were lost early in the disease and the loss was associated with disease activity. These findings have implications for the management of patients with rheumatoid arthritis and possibly other inflammatory diseases.

A new concept of the pathogenesis and natural course of osteoporosis is described, based on histomorphometric evaluation of iliac crest bone biopsies of 108 patients with untreated primary osteoporosis. It is suggested that primary osteoporosis spontaneously runs a three-phase course: during the initial period of negative bone balance, bone mass falls below the normal range; during the second phase bone mass remains consistently below age-related normal values; in the third phase restitution of osteoporosis is introduced by a positive bone balance. It is suggested that only about a quarter of patients with a skeletal mass below the age-related normal range have true primary osteoporosis; the remaining three-quarters may have secondary forms of osteoporosis where the underlying disease responsible for the bone loss had been missed before the osteoporosis was diagnosed.

A new radioimmunoassay technique was used to measure plasma-calcitonin in normal subjects. Plasma-calcitonin concentrations in women were less than 25% of those in men, and were often undetectable. However, during pregnancy or administration of the oestrogen-progestagen contraceptive pill, plasma-calcitonin equalled or exceeded male concentrations. These findings are consistent with an effect on calcitonin production of normal male testosterone concentrations and concentrations of the sex steroids during pregnancy. Calcitonin may protect the skeleton during calcium stress. Further, although it is unknown whether a deficiency of the hormone plays a role in postmenopausal osteoporosis, this is now a definite possibility which requires urgent investigation.

To explore the possibility that the wide variation in bone loss among oophorectomised women might be due to differences in adrenal androgens or their biosynthetic pathways, 18 women (10 with very fast and 8 with very slow bone loss) were selected. Serum levels of nine adrenal steroids, including the major androgens and cortisol, were measured under basal conditions and after overnight suppression followed by acute corticotropin stimulation. In addition, basal serum oestrone, oestradiol, dehydroepiandrosterone sulphate, sex-hormone-binding-globulin, corticosteroid binding globulin, and urinary free cortisol were measured. The only significant differences found were that women who lost bone rapidly had significantly higher urinary free-cortisol excretion (p less than 0.001) and a paradoxically diminished cortisol response to corticotropin. These data make it unlikely that endogenous adrenal androgens or oestrogens are a major factor in preventing bone loss after cessation of ovarian function; cortisol by its catabolic effect, however, may be a significant factor in causing osteoporosis.

Fracture surveys in the Johannesburg metropolitan area showed that the rate of femoral-neck fractures rose sharply after the climacteric in Caucasians, whereas the incidence of such fractures in African Negroes of the same age was almost negligible. However, a parallel epidemiological survey of metacarpal bone density in random samples of the same populations showed that absolute values for skeletal mass and bone density were greater in the Caucasians through most of the age-range from 5 to 75 years. Also, although bone density increased more rapidly and reached higher maximum values in young Caucasians than in Africans, it fell more rapidly in the former from the fourth decade onwards. The differences in the pattern of bone density alone are unlikely to account for the large difference in the fracture rates in the two populations. Perhaps quantitative changes in bone mass associated with ageing are accompanied by qualitative changes which may be critical in determining the liability to fracture.

To test whether mobilisation of immunoreactive calcitonin in response to calcium challenge is reduced in postmenopausal osteoporosis, seventeen postmenopausal osteoporotic women with compression fractures and ten normal age-matched women were given intravenous infusions of 3 mg/kg elemental calcium over a 10 min period. Blood samples were obtained 5 min before and at 0, 10, 20, and 60 min after start of infusion for the measurement of serum calcium and plasma immunoreactive calcitonin. Serum calcium increased significantly from baseline in both normal and osteoporotic groups; immunoreactive calcitonin increased significantly in the controls 10 min and 20 min after the start of infusion, but in the women with osteoporosis calcitonin levels did not change significantly at any time. 20 min after the start of infusion the change in immunoreactive calcitonin from baseline was significantly less in osteoporotic women than in the controls. These data are consistent with a decreased immunoreactive calcitonin response to calcium infusion in postmenopausal osteoporotic women, and suggest that calcitonin deficiency may be involved in the development of postmenopausal osteoporosis.

The density of bone in the distal third of the radius was measured in 13 men and 17 women with primary hyperparathyroidism. The bone density was significantly reduced (as compared to age-matched controls) in 7 of 11 postmenopausal women. However, it was reduced in only 2 of 13 men and in 1 of 6 premenopausal women. Thus, most of the postmenopausal women with primary hyperparathyroidism had low bone density, whereas most men and premenopausal women with this condition had normal bone density. The results support the conclusion that oestrogen deficiency may contribute to the development of bone disease by sensitising bone to the action of parathyroid hormone.