First Report® American College of Rheumatology/Association of Rheumatology Health Professionals Meeting

San Francisco, CA, October 24-29, 2008

Denosumab Associated With Significant Increases in Bone Mineral Density in Patients With Osteoporosis Previously Treated With Alendronate

San Francisco— In patients with osteoporosis previously treated with alendronate, switching to denosumab is associated with a significant increase in bone mineral density (BMD) as well as a rapid and significant reduction in serum CTX, report investigators at the American College of Rheumatology/Association of Rhematology Health Professionals (ACR/ARHP) Annual Scientific Meeting.

Because of the chronic nature of osteoporosis and the frequent need for long-term treatment to reduce fracture risk and maintain BMD, a better understanding of the safety and efficacy of switching patients from standard bisphosphonate therapies to newer therapies is needed. Denosumab, a fully monoclonal antibody directed against an essential mediator of osteoclast formation, function, and survival (the RANK ligand), has been shown to increase BMD in postmenopausal women with low bone mass as well as treatment-naïve patients.

To evaluate the safety and efficacy of transitioning patients with osteoporosis from a bisphosphonate such as alendronate to denosumab, Jacques P. Brown, MD, CHUQ, Laval University, Quebec City, Canada, and colleagues conducted an international multicenter, double-blind study in which postmenopausal women with low BMD previously treated with alendronate were randomized to continued treatment with alendronate (n = 251) or denosumab (n = 253). Eligibility criteria included prior treatment with branded or generic alendronate (70 mg once weekly) or equivalent for at least 6 months prior to screening and a BMD measurement corresponding to a T-score of ≤ -2.0 and ≥ -4.0 at the lumbar spine or proximal femur (ie, total hip).

Patients excluded from the study included those with any disease or condition known to affect bone metabolism, prior use of IV bisphosphonate, and vitamin D level of < 20 ng/mL. Patients who met study criteria and participated in the study had a mean age of 67.7 years, a mean lumbar spine BMD T-score of -2.63, and received prior bisphosphonate therapy for a median of 36 months.

Prior to randomization, all patients received open-label alendronate (70 mg once weekly) during a 1-month run-in phase. Patients were then randomized to continued branded alendronate or denosumab (60 mg every 6 mo). All patients also received daily calcium and vitamin D supplements.

At 12 months, the study found a significantly greater increase in total hip BMD from baseline in patients who switched to denosumab compared to those who continued on alendronate (1.90% vs 1.05%; P < 0.0001).

Patients treated with denosumab also showed significant gains in BMD at the lumbar spine, femoral neck, and trochanter as compared to those treated with alendronate (P < 0.03), and these gains were noted as early as 6 months from treatment initiation.  At 12 months, all skeletal sites showed a significant gain in BMD in the denosumab-treated patients (P < 0.01).

The study also found that denosumab significantly reduced serum CTX levels, a biochemical marker of bone turnover in serum, as compared to alendronate beginning 5 days after treatment and at all points throughout the study (P < 0.0001). In the patients who continued on alendronate, serum CTX levels remained near baseline levels.

The study found no differences in adverse events between the two treatment groups, with 197 adverse events (15 serious events) reported with denosumab and 196 adverse events (16 serious events) reported with alendronate. No patient reported hypocalcemia.

According to the authors, “these results suggest that the different mechanisms of inhibiting bone turnover between the two drugs may translate to measurable differences in indicators of drug effect.”
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Interventions Needed to Reduce Projected Increases in Medical Care Expenditures For Persons With Arthritis and Other Rheumatic Conditions

San Francisco—New data showing that medical expenditures for patients with arthritis and other rheumatic conditions (AORC) increased at a near constant rate annually above medical inflation between 1997 and 2005 suggest that future medical expenditures will continue to increase for these patients, creating a need for interventions to reduce these costs.

Miriam G. Cisternas, MGC Data Services, Carlsbad, CA, and colleagues presented data showing an average annual increase of 2.8% above medical inflation in overall medical expenditures between 1997 and 2005 for people with AORC.

Using data from the Medical Expenditure Panel Survey (MEPS)—a representative survey of the civilian, noninstitutionalized population of the United States—the investigators estimated overall annual medical care expenditures for people with AORC between 1997 and 2005, as well as expenditures based on type of medical care cost (ie, inpatient, ambulatory, prescription medications, home health, emergency room, and other). The study also looked at these expenditures in two subgroups of people, AORC people with no other chronic conditions (AORC Only) and AORC with other comorbid conditions (AORC Plus).

The study found a consistent annual increase in the number of people diagnosed with AORC through the study period, with an overall 22% increase from 36.8 million in 1997 to 44.9 million in 2005. This increase was attributed to an increase in the AORC Plus subgroup (ie, those with comorbid conditions), which rose from 31.8 to 40.3 million during this time period. The AORC Only subgroup remained relatively stable during this period, from 5.0 million in 1997 to 4.7 million in 2005.

Aggregate total medical expenditures for people with AORC during this period increased from $252.5 billion in 1997 to $353.0 billion in 2005, representing a 40% increase. This increase was completely attributable to expenditures incurred by the AORC Plus population, which increased from $244.5 to $342.7 billion. Aggregate costs fluctuated in the AORC Only group during this period.

In terms of individual costs, after a decrease between 1997-1998 from $6,848 to $6,141, the annual mean overall medical expenditures increased steadily from $6,848 in 1997 to $7,854 in 2005. This represents an average annual increase of $196 (2.8%) above medical inflation. Again, this annual increase was attributed primary to the AORC Plus subgroup that incurred a steady increase to $8,512 in 2005 after an initial decrease in 1998 of $6,908. The annual mean medical expenditures fluctuated slightly during this period for the AORC Only subgroup.

The study also found that ambulatory care visits and prescription medications accounted for most of the increased expenditures during this period. Ambulatory care expenditures, although fairly constant during 1997 to 2000, significantly increased from a mean cost of $1,855 in 2000 to $2,240 in 2001. After 2001, ambulatory expenses were nearly identical to inpatient expenditures ($2,240 and $2,193, respectively). Prescription medications averaged $970 in 1997 (or 14% of overall expenditures) and nearly doubled in 2005 to a mean of $1,811 (or 23% of overall expenditures).

Based on these findings that show an increase in both the individual and societal medical expenditures among adults with AORC, the investigators suggest that there is an “urgent need for clinical and public health interventions to reduce these impacts.”
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Study Suggests Low Vitamin D Doubles Prevalence of Radiographic Hip Osteoarthritis

San Francisco—Vitamin D insufficiency can be common in elderly men and has been linked to increased risk of osteoarthritis (OA). Results of a recent observational study suggest that older men with low serum 25-hydroxyvitamin D (25-OH D) levels are twice as likely to have prevalent radiographic hip OA (RHOA).

The results were reported by investigators led by Ramani Krishna Chaganti, MD, of the Hospital for Special Surgery, New York, NY, during a poster session at the ACR meeting. Their objective was to determine whether there is a cross-sectional association between serum vitamin D levels and the prevalence of arthritis of the hip. They also looked for a relationship between vitamin D levels and muscle strength. The authors cited previous observations of an association between serum vitamin D levels and worsening radiographic hip OA in elderly women.

The investigators obtained pelvic radiographs from a study group consisting of male patients aged 65 years or older from the Mr. OS study at visit 2 of the 7-year study, which was 4.7 years after the baseline date. Fasting morning blood samples were drawn and assessed for serum vitamin D levels from a random sample of 1608 participants. Pelvic X-rays were performed on 1104 of these subjects. Serum 25-OH D was also measured using LC-MS. A Nottingham power rig and 6-meter timed walk were used to measure muscle strength in the lower extremities.

RHOA was defined a summary score of ≥ 2 (range, 0-4). Insufficient vitamin D was defined as within the range of 15-30 ng/mL, and deficient vitamin D was defined as <15 ng/mL. Sufficient vitamin D was defined as > 30 ng/mL.

Collected data were subjected to logistic regression, which adjusted for age, clinic site, season of vitamin D measurement, and hip pain. The possible association between serum 25-OH D with prevalent RHOA was assessed with results from the timed 6-meter walk. A smaller subset of subjects with prevalent RHOA was assessed for association between 25-OH D levels and musculoskeletal strength. This analysis was performed using results from the Nottingham power rig and 6-meter timed walk.

At Visit 2, 996 men had no RHOA as determined by radiography scores < 2. Of those men without RHOA, 65% had a 25-OH D insufficiency compared with and 77% of men with RHOA who had 25-OH D insufficiency.

Other than a slower 6-meter walk speed (P = .02), and more hip pain (P < .0001) for men with RHOA, the investigators did not find a significant differences in age, body mass index, hip bone mineral density, or health status between men with and without RHOA. There was an association of higher 25-OH D levels and a lower prevalence of RHOA. The odds of prevalent RHOA were increased 2-fold for men with insufficient serum 25-OH D compared with men observed to have sufficient vitamin D. There was no significant association between serum vitamin D levels and either measure of muscle strength in the subset of men with prevalent RHOA.

After adjustment for age, clinic, season of vitamin D draw, and hip pain the odds ratio (OR) for developing RHOA was 2.20 (95% confidence interval [CI], 1.21-4.00; P = .01) for men with insufficient vitamin as compared with men who had sufficient vitamin D. The OR for men with deficient vitamin D developing RHOA was 2.43 (95% CI, 1.03-5.74; P = .04).

Similar results were obtained when these results were adjusted for the timed 6-meter walk. The OR for developing RHOA was 2.1 (95% CI, 1.15-3.8; P = .02) for men with insufficient vitamin as compared with men who had sufficient vitamin D. The OR for men with deficient vitamin D developing RHOA was 2.23 (95% CI, 0.93-5.3; P = .07).
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Older Women With Painful Radiographic Hip Osteoarthritis Report Sleep Disturbances

San Francisco—Chronic pain states such as osteoarthritis (OA) can adversely affect sleep quality, which impacts physical function and health status. The purpose of this study was to evaluate sleep disturbances in elderly women with radiographic hip OA (RHOA) or hip pain.

Investigators led by Nancy E. Lane, MD, University of California, Davis, performed two cross-sectional studies using data from the Study of Osteoporotic Fractures. In the first study, 90 women with painful RHOA and 3429 women without hip pain or RHOA were assessed for self-reported difficulty maintaining sleep ascertained 2 years after pelvic hip x-rays were obtained (1995-1997). RHOA was defined as summary grade ≥ 2 (range, 0-4) generated from pelvic radiographs scored for individual radiographic features. Hip pain was defined as pain on most days of the month.

In the second study, 362 women with self-reported moderate to extreme hip pain while walking and 2409 women with less or no pain were assessed for sleep efficiency and wake after sleep onset measured by wrist actigraphy for 3 to 5 days (2002-2003). Women with moderate/extreme hip pain when sitting (N = 297) or in bed (N = 337) were also analyzed. All analyses excluded women with history of total hip replacements or hip fractures. Covariates were obtained by questionnaire at the corresponding clinic visit. Logistic regression and linear regression were used for binary and continuous sleep outcomes, respectively.

In the first study, study subjects were aged ≥ 81 years. Women with painful RHOA were more likely to report difficulty with sleep maintenance as compared to women without pain or RHOA (age-adjusted OR = 2.1; 95% CI, 1.3-3.3). This association was attenuated, but remained elevated after adjustment for nonhip pain, rheumatoid arthritis (RA), depression, medication use and health status (OR = 1.6; 95% CI, 1.0-2.7).

In the second study, in multivariate models adjusted for age, race, BMI, RA and non hip pain, there was a 3% (95% CI, -4.6-1.1) reduction in mean sleep efficiency and 8.4-minute (95% CI, 3.0-13.8) increase in total time of wake after onset of sleep in women with moderate/extreme hip pain while walking as compared to those with less or no hip pain. These associations for both sleep measures remained significant after adjustment for health status, medication use and depression (P = 0.02). Results were similar for women who reported hip pain when sitting and or in bed.

The investigators concluded that elderly women with painful hip OA have increased subjectively reported sleep disturbances, and women who experience hip pain while walking have increased objectively measured sleep disturbances. However, some effect sizes are small in magnitude and may not be clinically significant. These results suggest that more aggressive treatment of hip pain may improve sleep quality in these individuals.
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Aging Patients With Systemic Lupus Erythematosus and Obstructive Sleep Apnea Vulnerable to Cognitive Dysfunction

San Francisco— Sleep apnea disorders are associated with serious neurocognitive dysfunction and regional alterations in brain morphology in humans.

Investigators led by Jamal A. Mikdashi, MD, from the University of Maryland, Rockville, hypothesized that aging patients with systemic lupus erythematosus (SLE) who had obstructive sleep apnea (OSA), characterized by intermittent nocturnal hypoxia and sleep fragmentation, are more susceptible to cognitive dysfunction than younger patients.

Of the 434 SLE patients followed at the Maryland Lupus Center, 26 elderly/late-onset SLE patients ([mean age, 69.9 + 4.8], 23 women, 17 African Americans) were compared to 196 young patients with SLE ([mean age, 42.9 + 10.6], 201 women, 149 African Americans). All patients were screened for sleep disorders, using the Epworth Sleepiness Scale, and those with abnormal score underwent basic sleep study. Patients (n = 212) who declined or did not have sleep study testing were excluded. Sleep apnea disorders were noted in 6/26 (3 mild, 3 severe) elderly lupus patients, and 26/196 (8 mild, 9 moderate, 9 severe) young patients. Standard neuropsychological testing was performed before and after treatment with 3 months of continuous positive airway pressure (CPAP). Comparison was done among aged and young SLE patients as well as 30 sex-, race-, education- matched non-SLE healthy controls with sleep apnea disorders.

Investigators found that obesity, daytime sleepiness, depression, cardio- and cerebrovascular symptoms, fatigue, OSA severity, and the other polysomnography variables were comparable among the groups. Prior to treatment, all patients with OSA showed cognitive impairment in information processing speed, alertness, attention and working memory, executive functioning, learning, and memory.

Aging patients with lupus displayed significant spatial learning impairments as compared with young patients and controls (P < 0.01). Independent predictors of cognitive dysfunction were associated with baseline disease activity (P < 0.015), hypertension (P < 0.043), and OSA (P < 0.003). Both aged and young patients with SLE improved with CPAP treatment on some individual neuropsychological test scores, although Digit Vigilance-Time showed significant improvement substantially greater in the young (P < 0.001).

These findings indicate unique vulnerability of the aging SLE patients with OSA to neurocognitive dysfunction. CPAP treatment of mild-to-moderate OSA in patients with SLE reduces the risk neurocognitive dysfunction, and is helpful in improving information processing speed, vigilance, and alertness.
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Study Finds Hip Fractures in Elderly Male Veterans Associated With High Rates of Mortality and Morbidity

San Francisco—Hip fractures are associated with significant morbidity and mortality in elderly men, and prior fracture increases the risk for future fracture significantly. A recent study has shown that bisphosphonate treatment after low-trauma hip fracture reduces recurrence and improves survival. The current rate of osteoporosis treatment after fracture is less than 10-20%.

The goal of this study led by Shabana Karim, MD, at the Veterans Affair Medical Center, Jackson, MS, was to review whether male veterans in the facility who had sustained low-impact hip fractures had osteoporosis screening and treatment before or within 3 months after their fracture. The study design was a retrospective analysis of male veterans identified through the data warehouse with diagnosis of hip fracture over a 3-year period (January 2005 through December 2007). Charts were reviewed, and patients with definite evidence of low-impact hip fractures within the study period were identified.

One hundred and fifteen male veterans were screened. Twenty-seven did not have a confirmed fragility fracture of the hip within the timeframe; 88 veterans did, with an average age of 78.5 years. Sixty-five were white males, 22 were African-American males, and 1 was of unknown race. Seventy-nine patients were admitted to the hospital, 68 had surgical intervention, and 63 had general medical consultations during hospitalization. Twelve patients (13.6%) died within 3 months of fracture.

Of the remaining 76 patients, 30 had inadequate local follow-up to determine whether they received screening or bisphosphonates post-fracture, often due to discharge to long-term care facilities. Forty-six patients had adequate local follow-up to determine screening and treatment. Of these 46, bisphosphonates were contraindicated in 4 due to renal disease. Only 3 of the remaining 42 patients (7.1%) received bisphosphonates within 3 months of fracture. Five were started on bisphosphonates more than 3 months post-fracture (average 19 mo). Two patients had post-fracture densitometry showing osteoporosis with bisphosphonates recommended but never started. One patient with documented osteoporosis and bisphosphonate therapy prior to fracture had no repeat densitometry or therapy after fracture. The remaining 31 patients (73.8%) had no densitometry or bisphosphonates before or after fracture.

The investigators concluded that hip fractures in elderly male veterans are associated with high rates of mortality and morbidity (as evidenced by the high number of deaths and transfers to long-term care facilities). They noted the difficulty in tracking these patients to assess if they received appropriate osteoporosis screening and treatment. A review of those patients with adequate records shows that they were significantly underscreened and undertreated.