Kenneth W. Lyles

Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture

BACKGROUND Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).

Association of osteoporotic vertebral compression fractures with impaired functional status

PURPOSE To determine if vertebral compression fractures in elderly women were associated with impairments in physical, functional, and psychosocial performance. SUBJECTS AND METHODS Ten white women with confirmed vertebral compression fractures were age- and race-matched with 10 control subjects without fractures in a case-control design. All subjects invited to participate in this study were patients of the Geriatrics Division of the Department of Medicine at Duke University Medical Center. All study participants lived either in the community or in the independent-living sections of local retirement communities in and around Durham, NC. Subjects with fractures (mean age = 81.9 years, SD = 5.9 years) had two or more vertebral compression fractures in their medical records, whereas control subjects (mean age = 79.6 years, SD = 6.5 years) had no history of vertebral fractures. Spinal radiographs of all women confirmed group assignment. Physical, functional, and psychosocial performances were evaluated. Physical performance was assessed by measurements of maximal trunk extension torque and thoracic and lumbar spinal motion in the sagittal plane, functional reach, mobility skills, 10-ft timed walk, and 6-minute walk test. Thoracic and lumbar spinal configurations were also determined. Functional performance was assessed using the Functional Status Index. Psychosocial performance was assessed with the following scales: Hopkins Symptom Checklist 90 Revised, Rosenberg Self-Esteem Scale, West Haven-Yale Pain Inventory, Beck Depression Inventory, and single-item health-belief questions. RESULTS Control subjects were not significantly different from patients with fractures in age, weight, number of current illnesses, number of prescribed medications, number of pain medications, ratings of lumbar spine degenerative disc disease, or lumbar spine facet joint arthritis. Activity levels and exercise participation were similar in both groups. Control subjects had no vertebral fractures, whereas fracture subjects had 4.2 +/- 2.6 fractures (range: 2 to 10). Thoracic kyphosis was increased and lumbar lordosis was reduced in fracture subjects. Fracture subjects had reduced maximal trunk extension torque, thoracic and lumbar spine sagittal plane motion, functional reach, mobility skills, and 6-minute walk test. The Functional Status Index showed reduced levels of functional performance in fracture subjects compared with controls with increased levels of assistance, pain with activity, and difficulty in activities. Psychosocial performance was limited in fracture subjects with increased psychiatric symptoms, increased pain, and greater perception of problems caused by health. CONCLUSION Vertebral compression fractures are associated with significant performance impairments in physical, functional, and psychosocial domains in older women.

Incidence and natural history of Paget's disease of bone in England and Wales.

This study used a large, primary care, record‐linkage resource (the General Practice Research Database [GPRD]) to evaluate the incidence, clinical presentation, and natural history of Pagets disease of bone in England and Wales. Between 1988 and 1999, we identified 2465 patients with the recorded diagnosis of Pagets disease of bone, within the five million subjects ≥18 years old who were registered in the GPRD. The validity of diagnostic recording was assessed by questionnaire to individual general practitioners (GPs) in 150 patients; the diagnosis was confirmed in 93.8% of responders. The mean age of patients with Pagets disease was 75 years and 51% were men. The prevalence of the disorder was 0.3% among men and women aged ≥55 years; incidence rates for clinically diagnosed Pagets disease rose steeply with age (men, 5 per 10,000 person‐years; women, 3 per 10,000 person‐years at the age of 75 years). Over the 11‐year period of the study, the age‐ and sex‐adjusted incidence rate of clinically diagnosed Pagets disease declined from 1.1 per 10,000 person‐years to 0.7 per 10,000 person‐years. Each patient with Pagets disease was matched to three controls matched by age, gender, and general practice. Cases had a greater risk of back pain (relative risk [RR], 2.1; 95% CI, 1.9‐2.3), osteoarthritis (OA; RR, 1.7; 95% CI, 1.5‐1.9), hip arthroplasty (RR, 3.1; 95% CI, 2.4‐4.1), knee arthroplasty (RR, 1.6; 95% CI, 1.0‐2.6), fracture (RR, 1.2; 95% CI, 1.0‐1.5), and hearing loss (RR, 1.6; 95% CI, 1.3‐1.9). Seven patients with Pagets disease developed a malignant bone neoplasm (0.3%). Using life table methodology, the estimated number of people who died within 5 years of follow‐up was 32.7% among the patients with Pagets disease and 28.0% among the control patients.

A Clinical Approach to Diagnosis and Management of Paget's Disease of Bone

PAGET’S DISEASE of bone (osteitis deformans) is a focal disorder of accelerated skeletal remodeling that can involve a single bone (monostotic) or multiple bones (polyostotic) and leads to bone hypertrophy, cortical expansion, and an abnormal bone structure responsible for bone pain and bone deformity and skeletal fragility. Complications of this disease can involve bones (deformity, fracture, and neoplastic degeneration), joints (osteoarthritis), the nervous system, and the vascular system. (1)

Long-Term Control of Bone Turnover in Paget's Disease With Zoledronic Acid and Risedronate

A single 5‐mg infusion of zoledronic acid restores biochemical markers of bone turnover into the reference range in the majority of patients with Pagets disease and maintains biochemical remission for at least 2 years. This effect is largely independent of pretreatment disease activity and prior bisphosphonate therapy.

Evaluation of a Role for 1,25-Dihydroxyvitamin D3 in the Pathogenesis and Treatment of X-linked Hypophosphatemic Rickets and Osteomalacia

Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristic of this disease. Thus, in the present study, we investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D(3) therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, ages 14-30 yr, had normocalcemia (9.22+/-0.06 mg/dl); hypophosphatemia (2.25+/-0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12+/-0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D(3) concentration was 33.9+/-7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D(3) was not increased, but was normal at 30.3+/-2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotypic expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the long-term response to pharmacological amounts of 1,25-dihydroxyvitamin D(3) therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D(3) in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. We, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D(3) is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotypic expression of this disease.

Calcification of Entheses Associated with X-Linked Hypophosphatemic Osteomalacia

We undertook a retrospective analysis of 26 patients with X-linked hypophosphatemic osteomalacia (or rickets), whose ages ranged from 1 to 62 years and who were from 11 different kindreds, to determine the prevalence and clinical characteristics of a unique disorder of the entheses (tendons, ligaments, and joint capsules). We found a generalized involvement of the entheses, with exuberant calcification of tendon and ligament insertions and of joint capsules, in 69 per cent of the subjects. The prevalence and extent of disease increased with age but were not correlated with sex. Commonly affected sites included the hand and sacroiliac joints. Histologic evaluation in a selected patient revealed intratendinous lamellar bone but no inflammatory cells. Our observations indicate that this disorder is an integral part of X-linked hypophosphatemic osteomalacia and exhibits clinical, radiographic, and histologic characteristics that differentiate it from degenerative disorders of these tissues and seronegative spondyloarthropathies.

Hypophosphatemic Osteomalacia: Association with Prostatic Carcinoma

Hypophosphatemic osteomalacia that remits after resection of a coexisting tumor has been described in 35 patients. Because the associated neoplasms have been of mesenchymal origin, it has been inferred that this tumor-induced osteomalacia syndrome is uniquely related to tumours of this derivation. However, in the present investigation we studied subjects with coincident hypophosphatemia and prostatic carcinoma to ascertain whether this endodermal malignancy causes the tumor-induced osteomalacia syndrome. The hypophosphatemic patients had renal phosphate wasting, gastrointestinal malabsorption of calcium and phosphate, and negative phosphate balance. Moreover, bone biopsies showed histomorphologic changes indicative of osteomalacia. Although widespread metastases precluded establishing the diagnosis of tumor-induced osteomalacia by resection of the tumor, a series of studied excluded alternate causes for the osteomalacia. Further, affected subjects had a normal serum concentration of 25-hydroxyvitamin D, 28.0 +/- 8.3 ng/mL, and serum 1,25-dihydroxyvitamin D levels were low, 15.0 +/- 1.0 pg/mL, characteristic of the tumor-induced osteomalacia syndrome. Thus, prostatic carcinoma, although an endodermal malignancy, may cause the tumor-induced osteomalacia syndrome.

Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.

Benefit of adherence with bisphosphonates depends on age and fracture type: results from an analysis of 101,038 new bisphosphonate users.

The relationship between high adherence to oral bisphosphonates and the risk of different types of fractures has not been well studied among adults of different ages. Using claims data from a large U.S. health care organization, we quantified adherence after initiating bisphosphonate therapy using the medication possession ratio (MPR) and identified fractures. Cox proportional hazards models were used to evaluate the rate of fracture among nonadherent persons (MPR < 50%) compared with highly adherent persons (MPR ≥ 80%) across several age strata and a variety of types of clinical fractures. In conjunction with fracture incidence rates among the nonadherent, these estimates were used to compute the number needed to treat with high adherence to prevent one fracture, by age and fracture type. Among 101,038 new bisphosphonate users, the proportion of persons with high adherence at 1, 2, and 3 yr was 44%, 39%, and 35%, respectively. Among 65‐ to 78‐yr‐old persons with a physician diagnosis of osteoporosis, the crude and adjusted rate of hip fracture among the nonadherent was 1.96 (95% CI, 1.48–2.60) and 1.74 (95% CI, 1.30–2.31), respectively, resulting in a number needed to treat with high adherence to prevent one hip fracture of 107. The impact of high adherence was substantially less for other types of fractures and for younger persons. Analysis of adherence in a non–time‐dependent fashion artifactually magnified differences in fracture rates between adherent and nonadherent persons. The antifracture effectiveness associated with high adherence to oral bisphosphonates varied substantially by age and fracture type. These results provide estimates of absolute fracture effectiveness across age subgroups and fracture types that have been minimally evaluated in clinical trials and may be useful for future cost‐effectiveness studies.