Ethel S. Siris

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

BACKGROUND Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery

BACKGROUND AND METHODS In the United States, most patients with primary hyperparathyroidism have few or no symptoms. The need for parathyroidectomy to treat all patients with this disorder has therefore been questioned. We studied the clinical course and development of complications for periods of up to 10 years in 121 patients with primary hyperparathyroidism, 101 (83 percent) of whom were asymptomatic. There were 30 men and 91 women (age range, 20 to 79 years). During the study, 61 patients (50 percent) underwent parathyroidectomy, and 60 patients were followed without surgery. RESULTS Parathyroidectomy in patients with or without symptoms led to normalization of serum calcium concentrations and a mean (+/-SE) increase in lumbar-spine bone mineral density of 8+/-2 percent after 1 year (P=0.005) and 12+/-3 percent after 10 years (P=0.03). Bone mineral density of the femoral neck increased 6+/-1 percent after 1 year (P=0.002) and 14+/-4 percent after 10 years (P=0.002). Bone mineral density of the radius did not change significantly. The 52 asymptomatic patients who did not undergo surgery had no change in serum calcium concentration, urinary calcium excretion, or bone mineral density. However, 14 of these 52 patients (27 percent) had progression of disease, defined as the development of at least one new indication for parathyroidectomy. All 20 patients with symptoms had kidney stones. None of the 12 who underwent parathyroidectomy had recurrent kidney stones, whereas 6 of the 8 patients who did not undergo surgery did have a recurrence. CONCLUSIONS In patients with primary hyperparathyroidism, parathyroidectomy results in the normalization of biochemical values and increased bone mineral density. Most asymptomatic patients who did not undergo surgery did not have progression of disease, but approximately one quarter of them did have some progression.

Adherence to Bisphosphonate Therapy and Fracture Rates in Osteoporotic Women: Relationship to Vertebral and Nonvertebral Fractures From 2 US Claims Databases

OBJECTIVE To characterize the relationships between adherence (complance and persistence) to bisphosphonate therapy and risk of specific fracture types in postmenopausal women. PATIENTS AND METHODS Data were collected from 45 employers and 100 health plans in the continental United States from 2 claims databases during a 5-year period (January 1, 1999, through December 31, 2003). Claims from patients receiving a bisphosphonate prescription (alendronate or risedronate) were evaluated for 6 months before the Index prescription and during 24 months of follow-up to determine total, vertebral, and nonvertebral osteoporotic fractures, persistence (no gap in refills for >30 days during 24 months), and refill compliance (medication possession ratio > or = 0.80). RESULTS The eligible cohort included 35,537 women (age, > or = 45 years) who received a bisphosphonate prescription. A subgroup with a specified diagnosis of postmenopausal osteoporosis was also evaluated. Forty-three percent were refill compliant, and 20% persisted with bisphosphonate therapy during the 24-month study period. Total, vertebral, nonvertebral, and hip fractures were significantly lower in refill-compliant and persistent patients, with relative risk reductions of 20% to 45%. The relationship between adherence and fracture risk remained significant after adjustment for baseline age, concomitant medications, and fracture history. There was a progressive relationship between refill compliance and fracture risk reduction, commencing at refill compliance rates of approximately 50% and becoming more pronounced at compliance rates of 75% and higher. CONCLUSIONS Adherence to bisphosphonate therapy was associated with significantly fewer fractures at 24 months. Increasing refill compliance levels were associated with progressively lower fracture rates. These findings suggest that incremental changes in medication-taking habits could improve clinical outcomes of osteoporosis treatment.

Fractures Attributable to Osteoporosis: Report from the National Osteoporosis Foundation

To assess the cost‐effectiveness of interventions to prevent osteoporosis, it is necessary to estimate total health care expenditures for the treatment of osteoporotic fractures. Resources utilized for the treatment of many diseases can be estimated from secondary databases using relevant diagnosis codes, but such codes do not indicate which fractures are osteoporotic in nature. Therefore, a panel of experts was convened to make judgments about the probabilities that fractures of different types might be related to osteoporosis according to patient age, gender, and race. A three‐round Delphi process was applied to estimate the proportion of fractures related to osteoporosis (i.e., the osteoporosis attribution probabilities) in 72 categories comprised of four specific fracture types (hip, spine, forearm, all other sites combined) stratified by three age groups (45–64 years, 65–84 years, 85 years and older), three racial groups (white, black, all others), and both genders (female, male). It was estimated that at least 90% of all hip and spine fractures among elderly white women should be attributed to osteoporosis. Much smaller proportions of the other fractures were attributed to osteoporosis. Regardless of fracture type, attribution probabilities were less for men than women and generally less for non‐whites than whites. These probabilities will be used to estimate the total direct medical costs associated with osteoporosis‐related fractures in the United States.

Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial.

Prevalent vertebral fractures and baseline bone mineral density (BMD) predict subsequent fracture risk. The objective of this analysis is to examine whether baseline vertebral fracture severity can predict new vertebral and nonvertebral fracture risk. In the randomized, double-blind 3-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis (low BMD or prevalent vertebral fractures) were randomly assigned to placebo, raloxifene 60 mg/day, or raloxifene 120 mg/day. Post hoc analyses studied the association between baseline fracture severity and new fracture risk in the placebo group and the effects of placebo, raloxifene 60 mg/day, and raloxifene 120 mg/day on new fracture risk in women with the most severe prevalent vertebral fractures (n = 614). Vertebral fracture severity was visually assessed using semiquantitative analysis of radiographs and categorized by estimated decreases in vertebral heights. Reported new nonvertebral fractures were radiographically confirmed. Baseline vertebral fracture severity predicted vertebral and nonvertebral fracture risk at 3 years. In women without prevalent vertebral fractures, 4.3 and 5.5% had new vertebral and nonvertebral fractures, respectively. In women with mild, moderate, and severe prevalent vertebral fractures, 10.5, 23.6, and 38.1% respectively had new vertebral fractures, whereas 7.2, 7.7, and 13.8% respectively experienced new nonvertebral fractures. Number of prevalent vertebral fractures and baseline BMD also predicted vertebral fracture risk, but the severity of prevalent vertebral fractures was the only predictor of nonvertebral fracture risk and remained a significant predictor after adjustment for baseline characteristics, including baseline BMD. In patients with severe baseline vertebral fractures, raloxifene 60 mg/day decreased the risks of new vertebral [RR 0.74 (95% Cl 0.54, 0.99); P = 0.048] and nonvertebral (clavicle, humerus, wrist, pelvis, hip, and leg) fractures [RH 0.53 (95% CI 0.29, 0.99); P = 0.046] at 3 years. To prevent one new fracture at 3 years in women with severe baseline vertebral fractures with raloxifene 60 mg/day, the number needed to treat (NNT) was 10 for vertebral and 18 for nonvertebral fractures. Similar results were observed in women receiving raloxifene 120 mg/day. In summary, baseline vertebral fracture severity was the best independent predictor for new vertebral and nonvertebral fracture risk. Raloxifene decreased new vertebral and nonvertebral fracture risk in the subgroup of women with severe vertebral fractures at baseline. These fractures may reflect architectural deterioration, independent of BMD, leading to increased skeletal fragility.

Osteoporosis and fracture risk in women of different ethnic groups.

Osteoporosis and 1‐year fracture risk were studied in 197,848 postmenopausal American women from five ethnic groups. Weight explained differences in BMD, except among blacks, who had the highest BMD. One SD decrease in BMD predicted a 50% increased fracture risk in each group. Despite similar relative risks, absolute fracture rates differed.

Paget's Disease of Bone

Pagets disease of bone is a localized disorder of bone remodeling. Increased numbers of larger than normal osteoclasts initiate the process at affected skeletal sites, and the increase in bone resorption is followed by an increase in new bone formation, altering bone architecture. The signs and symptoms of Pagets disease are varied, depending in part on the location of the involved sites and the degree of increased bone turnover. Recent progress in Pagets disease research includes new data regarding the etiology of this disorder and the ongoing development of more effective therapies. Although the cause of Pagets disease remains unproven, the creation of pagetic osteoclasts seems ever more likely to result from both genetic and environmental factors. Many studies indicate that in patients with Pagets disease, both osteoclasts and their precursors harbor evidence of a paramyxovirus infection, although not all studies confirm this finding. Very recent genetic investigations have identified one candidate gene on chromosome 18q, although genetic heterogeneity is almost certainly present. Advances in treatment have resulted from the availability of several potent bisphosphonate compounds (e.g., pamidronate, alendronate, and risedronate) that, unlike earlier treatments, produce normal or near normal bone turnover indices in a majority of patients. New bone formation after such treatment has a more normal, lamellar pattern, and mineralization abnormalities are rare to absent with the newer compounds. The availability of such agents has prompted a more aggressive management philosophy in which both symptomatic disease and also asymptomatic disease at sites with a risk of progression and future complications are viewed as clear indications for pharmacologic intervention.

The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years.

CONTEXT Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue. OBJECTIVE The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr. DESIGN The study had an observational design. SETTING The setting was a referral center. PATIENTS Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic. INTERVENTION Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery. MAIN OUTCOME MEASURE BMD was measured. RESULTS Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 +/- 3% (mean +/- sem; P < 0.05) at the femoral neck, and 35 +/- 5%; P < 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-seven percent of asymptomatic patients showed disease progression (one or more new guidelines for surgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict who would have progressive disease. BMD increases in patients who underwent surgery were sustained for the entire 15 yr. CONCLUSIONS Parathyroidectomy led to normalization of biochemical indices and sustained increases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meeting surgical criteria at the outset did not predict this progression. Cortical bone density decreased in the majority of subjects with additional observation time points and long-term follow-up. These results raise questions regarding how long patients with PHPT should be followed up without intervention.

Obesity is not protective against fracture in postmenopausal women: GLOW

OBJECTIVE To investigate the prevalence and incidence of clinical fractures in obese, postmenopausal women enrolled in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS This was a multinational, prospective, observational, population-based study carried out by 723 physician practices at 17 sites in 10 countries. A total of 60,393 women aged ≥ 55 years were included. Data were collected using self-administered questionnaires that covered domains that included patient characteristics, fracture history, risk factors for fracture, and anti-osteoporosis medications. RESULTS Body mass index (BMI) and fracture history were available at baseline and at 1 and 2 years in 44,534 women, 23.4% of whom were obese (BMI ≥ 30 kg/m(2)). Fracture prevalence in obese women at baseline was 222 per 1000 and incidence at 2 years was 61.7 per 1000, similar to rates in nonobese women (227 and 66.0 per 1000, respectively). Fractures in obese women accounted for 23% and 22% of all previous and incident fractures, respectively. The risk of incident ankle and upper leg fractures was significantly higher in obese than in nonobese women, while the risk of wrist fracture was significantly lower. Obese women with fracture were more likely to have experienced early menopause and to report 2 or more falls in the past year. Self-reported asthma, emphysema, and type 1 diabetes were all significantly more common in obese than nonobese women with incident fracture. At 2 years, 27% of obese women with incident fracture were receiving bone protective therapy, compared with 41% of nonobese and 57% of underweight women. CONCLUSIONS Our results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures.

The effect of age and bone mineral density on the absolute, excess, and relative risk of fracture in postmenopausal women aged 50–99: results from the National Osteoporosis Risk Assessment (NORA)

IntroductionThis study evaluates the effect of age and bone mineral density (BMD) on the absolute, excess, and relative risk for osteoporotic fractures at the hip, wrist, forearm, spine, and rib within 3 years of peripheral BMD testing in postmenopausal women over a wide range of postmenopausal ages.MethodsData were obtained from 170,083 women, aged 50–99 years, enrolled in the National Osteoporosis Risk Assessment (NORA) following recruitment from their primary care physicians’ offices across the United States. Risk factors for fracture and peripheral BMD T-scores at the heel, forearm, or finger were obtained at baseline. Self-reported new fractures at the hip, spine, rib, wrist, and forearm were obtained from questionnaires at 1- and 3-year follow-ups. Absolute, excess (attributable to low BMD), and unadjusted and adjusted relative risks of fracture were calculated.ResultsAt follow-up, 5312 women reported 5676 fractures (868 hip, 2420 wrist/forearm, 1531 rib, and 857 spine). Absolute risk of fracture increased with age for all fracture sites. This age-effect was most evident for hip fracture – both the incidence and the excess risk of hip fracture for women with low BMD increased at least twofold for each decade increase in age. The relative risk for any fracture per 1 SD decrease in BMD was similar across age groups (p>0.07). Women with low BMD (T-score <−1.0) had a similar relative risk for fracture regardless of age.ConclusionsAt any given BMD, not only the absolute fracture risk but also the excess fracture risk increased with advancing age. Relative risk of fracture for low bone mass was consistent across all age groups from 50 to 99 years.