Association of prior treatment with nitrogen-containing bisphosphonates on outcomes of COVID-19 positive patients.

COVID-19 infection has resulted in significant morbidity and mortality globally, especially among older adults. Repurposed drugs have demonstrated activity in respiratory illnesses, including nitrogen-containing bisphosphonates. In this retrospective longitudinal study at 4 academic medical centers, we show no benefit of nitrogen-containing bisphosphonates regarding ICU admission, ventilator use, and mortality among older adults with COVID-19 infection. We specifically evaluated the intravenous bisphosphonate zoledronic acid and found no difference compared to oral bisphosphonates. BACKGROUND: Widely used in osteoporosis treatment, nitrogen-containing bisphosphonates (N-BP) have been associated with reduced mortality and morbidity among older adults. Based on prior studies, we hypothesized that prior treatment with N-BP might reduce intensive care unit (ICU) admission, ventilator use, and death among older adults diagnosed with COVID-19. METHODS: This retrospective analysis of the PCORnet Common Data Model across 4 academic medical centers through 1 September 2021 identified individuals age >50 years with a diagnosis of COVID-19. The composite outcome included ICU admission, ventilator use, or death within 15, 30, and 180 days of COVID-19 diagnosis. Use of N-BP was defined as a prescription within 3 years prior. ICU admission and ventilator use were determined using administrative codes. Death included both in-hospital and out-of-hospital events. Patients treated with N-BP were matched 1:1 by propensity score to patients without prior N-BP use. Secondary analysis compared outcomes among those prescribed zoledronic acid (ZOL) to those prescribed oral N-BPs. RESULTS: Of 76,223 COVID-19 patients identified, 1,853 were previously prescribed N-BP, among whom 559 were prescribed ZOL. After propensity score matching, there were no significant differences in the composite outcome at 15 days (HR 1.22, 95% CI: 0.89-1.67), 30 days (HR 1.24, 95% CI: 0.93-1.66), or 180 days (HR 1.17, 95% CI: 0.93-1.48), comparing those prescribed and not prescribed N-BP. Compared to those prescribed oral N-BP, there were no significant differences in outcomes among those prescribed ZOL. CONCLUSION: Among older COVID-19 patients, prior exposure to N-BP including ZOL was not associated with a reduction in ICU admission, ventilator use, or death.

Zoledronic acid reduces the rate of clinical fractures after surgical repair of a hip fracture regardless of the Pretreatment bone mineral density.

In patients with surgical repair of a low-trauma hip fracture, zoledronic acid (ZA) reduced the risk of subsequent fractures regardless of pretreatment femoral neck and total hip bone mineral density (BMD). INTRODUCTION: Zoledronic acid reduces the risk of subsequent fractures after repair of a hip fracture. It is still unclear whether the benefits in fracture reduction with ZA depend upon hip bone mineral density at the time of fracture. METHODS: We preformed additional post hoc analyses of data from the HORIZON Recurrent Fracture Trial to determine if ZA treatment reduced the risk of new clinical fractures regardless of pretreatment BMD. We modeled femoral neck and total hip BMD as both continuous and dichotomous variables (BMD T-score above and below -2.5). RESULTS: There are no evidence that baseline femoral neck and total hip BMD modified the anti-fracture efficacy of ZA when pretreatment BMD was analyzed as a continuous or a dichotomous variable (interaction p-values > 0.20). The clinical fracture efficacy of ZA was similar among patients with pretreatment femoral neck BMD values above and below -2.5 (relative hazards = 0.60 and 0.67, respectively, interaction p-value = 0.95). A similar result was obtained using pretreatment total hip BMD values (relative hazards = 0.72 and 0.57, respectively, interaction p-value = 0.41). CONCLUSION: There data should provide more comfort in prescribing ZA after surgical repair of a hip fracture, regardless of pretreatment BMD.

Fracture prevention in patients with cognitive impairment presenting with a hip fracture: secondary analysis of data from the HORIZON Recurrent Fracture Trial.

UNLABELLED: Patients with cognitive impairment (CI) often do not receive secondary fracture prevention. Use of zoledronic acid led to a similar reduction in re-fracture risk but the survival benefit was limited to those without CI. INTRODUCTION: We tested whether the effects of zoledronic acid (Zol) on re-fracture and mortality differed in patients presenting with a hip fracture by cognitive status. METHODS: We used data from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial, of yearly intravenous 5 mg Zol vs. placebo in patients presenting with a hip fracture. Primary outcome was new fracture and secondary outcome mortality. Short Portable Mental Status Questionnaire (SPMSQ) with a cut-point of >2 was used to identify CI. Fine-Gray models for competing events were fitted to study the effect of Zol on re-fracture and Cox regression for death. A multiplicative term was introduced to study a potential interaction between treatment and cognitive status on outcomes. RESULTS: Baseline SPMSQ of 1,966/2,127 (92.4%) patients was measured. Three hundred fifty (17.8%) had CI, balanced between treatment arms. In the placebo arm, there was similar fracture incidence between those with and without CI (15.4 vs. 12.3%, p = 0.26). There was no significant interaction for the effect of CI on Zol and re-fracture (p = 0.66). CI was associated with higher 1-year mortality (12.6 vs. 4.3%, p < 0.001) and the interaction was bordering significance (interaction, p = 0.066). Zol prolonged survival only in patients with normal cognitive status [HR 0.56 (95% CI 0.40-0.80)] and not in those with CI [HR 0.90 (95% CI 0.59-1.38)]. CONCLUSIONS: While these results require confirmation, the findings support the use of bisphosphonates in patients with osteoporotic fracture and CI expected to live for more than 6 months.

Association between timing of zoledronic acid infusion and hip fracture healing.

UNLABELLED: Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period. INTRODUCTION: Intravenous zoledronic acid 5 mg (ZOL) given after a hip fracture reduces secondary fracture rates and mortality. It has been postulated that bisphosphonates may affect healing if given soon after a fracture. We sought to determine whether the timing of ZOL infusion affected the risk of delayed hip fracture healing. METHODS: In the HORIZON Recurrent Fracture Trial, patients were randomized within 90 days of a low-trauma hip fracture to receive either once-yearly ZOL (n = 1,065) or placebo (n = 1,062). Clinical symptoms of delayed hip fracture healing were sought at randomization, 6 months and 12 months after fracture; if present, a central adjudication committee blinded to treatment assignment reviewed radiographs and clinical records. Median follow-up was 1.9 years. RESULTS: The overall incidence of delayed healing was 3.2% (ZOL) and 2.7% (placebo; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.72-1.90; p = 0.61). Logistic regression models revealed no association between ZOL and delayed healing even after adjusting for other risk factors (OR, 1.21; 95% CI, 0.74-1.99; p = 0.44). There was no interaction by timing of infusion, and nonunion rates were similar even when ZOL was given within 2 weeks of hip fracture repair. NSAID use was significantly associated with delayed fracture healing (OR, 2.55; 95% CI, 1.49-4.39; p < 0.001). CONCLUSIONS: ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period.

Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON-Recurrent Fracture Trial.

UNLABELLED: This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON-RFT. At month 24 and end of the study visit, ZOL significantly improved patients' overall health state compared to placebo as assessed by the EQ-5D VAS. INTRODUCTION: To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT). METHODS: In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5 mg (n = 1,065) or placebo (n = 1,062) within 90 days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months 6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables. RESULTS: At baseline, patients (mean age 75 years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67 ± 0.56 vs. 5.42 ± 0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86 ± 4.91 vs. -1.69 ± 3.42), non-vertebral fractures (5.03 ± 2.48 vs. -1.07 ± 2.16), and clinical fractures (5.19 ± 2.25 vs. -0.72 ± 1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p = 0.6238), self-care (4.92% vs. 6.69%; p = 0.1013), and usual activities (10.28% vs. 12.91%; p = 0.0775). CONCLUSION: ZOL significantly improves HRQoL in patients with low-trauma hip fracture.

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.

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.

What is the clinical significance of bone loss in primary hyperparathyroidism?

To help determine the clinical significance of the bone loss associated with primary hyperparathyroidism, we studied the prevalence of vertebral fractures in a group of patients with this disorder. From a registry of parathyroidectomies, 206 cases were reviewed, and lateral chest roentgenograms were studied for the presence of fractures. All roentgenograms were interpreted by two of the investigators who were "blinded" to diagnoses. Comparisons of readings were made that assured interrater agreement. A group of patients who underwent cholecystectomy served as controls. Studied in a logistic regression analysis model, controlling for the effects of age, sex, and race, primary hyperparathyroidism was found to be significantly associated with vertebral fractures. Subgroup analyses performed on the patients with hyperparathyroidism failed to identify specific biochemical or clinical markers associated with fractures. Our results suggest that the bone loss of primary hyperparathyroidism is clinically significant, leading not only to decreased bone densities but also to an increased prevalence of fractures.

Paget's disease of bone and quality of life.

Little is known about how Paget's disease of bone affects quality of life. To better understand the relative impact of factors on quality of life, we mailed a brief survey to 2000 people randomly selected from the Paget's Foundation mailing list. The sample was geographically stratified to examine the effects of specialist availability. Nine hundred and fifty-eight persons responded to the questionnaire (53% response rate after adjustment for death, incorrect addresses, and nondeliverable mailings). The sample had equal proportions of males and females, with a mean age of 74 years (SD = 9.0). Most (97%) were white, with high levels of education (mean 13 years; SD 3.7) and income (60% earned more than $20,000 annually). They reported pagetic bone in the skull (34%), spine (35%), pelvis (49%), and leg (48%). The most frequently mentioned complications were hearing loss (37%) and bowed limbs (31%). Comorbidity included arthritis (64%), hypertension (32%), and heart problems (28%). Nearly half (47%) reported feelings of depression, and 42% said that their health was fair or poor. Only 21% reported that quality of life was very good or excellent. In multiple partial F-test regression analyses, variables were divided into four domains (social, psychological, care, and biomedical). The psychological domain explained 19% of the variance beyond that explained by all other variables; the social domain explained 3%, the biomedical domain explained 3% and the care domain explained 1%. The importance of the psychological aspects of Paget's disease suggests that treatment protocols should include psychological intervention to improve quality of life.

Factors associated with self-rated health in patients with Paget's disease of bone.

Multiple studies show that poor self-rated health (SRH) increases the risk of mortality up to 5-fold when compared to excellent SRH. This powerful association remains even with objective health status and risk factors controlled. However, few studies have examined the determinants of SRH, especially as they relate to specific chronic diseases. Here we identify personal characteristics and disease-related attributes that are strongly associated with SRH in a sample of patients with Paget's disease of bone to determine whether any factors can be modified. Two thousand people randomly selected from the Paget Foundation mailing list received a survey asking for information on demographics, general health and functioning, and the impact of Paget's disease. Nine hundred and fifty-eight PD patients returned the completed survey and answered the question, "How would you rate your overall health?" Answers ranged from excellent (1) to poor (5). Ordinary least squares regression was used, with SRH as the dependent variable, to identify those variables significantly associated with SRH. The overall regression model was significant (p = 0.0001; R2 = 0.44). Age (p = 0. 005), satisfaction with family help (p = 0.0001), number of comorbid conditions (p = 0.0001), functional limitations (p = 0.0003), disease impact (p = 0.0002), health compared to 5 years ago (p = 0. 0001), and depressive symptoms (p = 0.012) were significant predictors. Of these, satisfaction with family help, functional limitations, disease impact, and depressive symptoms are potentially modifiable with appropriate interventions. Future longitudinal studies should examine the effectiveness of such interventions in improving SRH.

Peyronie's disease is associated with Paget's disease of bone.

Peyronie's disease is an idiopathic disorder in which an inflammatory fibrosis occurs in the tunica albuginea of the corpora cavernosa which causes the erect penis to become deformed. Peyronie's disease has a prevalence of 1% in men over age 50 years. Paget's disease of bone is a chronic skeletal disease with areas of increased bone turnover leading to pain, deformity, and in some cases arthritis. Because of a high rate of Peyronie's disease in subjects in a Paget's disease industry-sponsored drug trial, we asked whether there was an association between Peyronie's disease and Paget's disease of bone. We evaluated 61 men with Paget's disease attending our clinic for metabolic bone disease in a tertiary referral hospital, reviewed hospital records of all men discharged from our three hospitals with the diagnosis of Peyronie's disease, and mailed a validated questionnaire about shape of the erect penis to 1500 male members of the Paget Foundation. In the clinic population of men with Paget's disease of bone, 51 of 61 (83.6%) reported having normal erections; 10 patients (16.4%) were impotent. Sixteen of the 51 men (31.4%) had developed a bend or deformity in their erect penis which was confirmed by a urologist's examination to be Peyronie's disease. When the men with Paget's disease with and without Peyronie's disease were compared, there was no difference in their ages, years with Paget's disease, or serum alkaline phosphatase level. Upon medical record review, 1 patient of 262 (0.4%) with Peyronie's disease was found to have Paget's disease of bone. The men with Paget's disease returned their questionnaires for a response rate of 44.8% and reported Peyronie's disease with a prevalence of 14.5%. We suggest that Peyronie's disease is associated with Paget's disease of bone. Furthermore, we suggest that Peyronie's disease may be a previously unrecognized complication of Paget's disease of bone.

Parathyroid hormone effects on serum 1,25-dihydroxyvitamin D levels in patients with X-linked hypophosphatemic rickets: evidence for abnormal 25-hydroxyvitamin D-1-hydroxylase activity.

Patients with X-linked hypophosphatemic rickets (XLH) have normal or marginally low serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels despite manifesting hypophosphatemia and phosphate depletion, which increase 1,25-(OH)2D production in many animal species. These data are consistent with the possibility that regulation of vitamin D metabolism is abnormal in XLH. However, controversy concerning the role of phosphate in the regulation of 25-hydroxyvitamin D-1-hydroxylase activity in man has raised doubt about this proposed defect. The presence of a defect in vitamin D metabolism could be established if hormonal or metabolic factors, other than hypophosphatemia, were unable to stimulate 25-hydroxyvitamin D-1-hydroxylase activity normally in patients with XLH. Thus, we compared the effects of parathyroid hormone infusion on serum 1,25-(OH)2D levels in patients with XLH and normals. In response to iv infusion of parathyroid extract (200 U at 0915 and 1700 h), the serum 1,25-(OH)2D concentration increased 218% above base line (from 34.0 +/- 3.0 to 108.8 +/- 2.5 pg/ml) in normals and only 68% (from 30.6 +/- 3.0 to 48.8 +/- 5.5 pg/ml) in patients with XLH. The disparate response occurred in spite of an equivalent increase in urinary cAMP excretion in the normals (from 3.00 +/- 0.14 to 8.70 +/- 0.25 mumol/g creatinine . 24 h) and XLH patients (from 3.10 +/- 0.39 to 8.30 +/- 1.0 mumol/g creatinine . 24 h) as well as equivalent decreases in the renal tubular maximum for the reabsorption of phosphate per liter glomerular filtrate (1.2 +/- 0.1 and 0.9 +/- 0.2 mg/dl, respectively). These observations support the possibility that regulation of vitamin D metabolism is abnormal in XLH.

Correlations of serum concentrations of 1,25-dihydroxyvitamin D, phosphorus, and parathyroid hormone in tumoral calcinosis.

The inherited metabolic disorder tumoral calcinosis is characterized by elevated serum phosphorus and 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels and paraarticular calcific tumors. The pathogenesis of this disease is obscure, but an elevated renal phosphate reabsorption threshold and increased production of 1,25-(OH)2D are postulated as defects. We studied nine affected patients and found that both serum phosphorus and renal phosphate reabsorption threshold (TmP/GFR) were positively correlated with serum 1,25-(OH)2D levels. Since tumoral calcinosis is a disorder with abnormal renal phosphate transport, we compared the TmP/GFR and serum 1,25-(OH)2D levels to values obtained in patients with two other diseases with renal phosphate transport defects: oncogenic osteomalacia and X-linked hypophosphatemic rickets. We found a significant correlation between TmP/GFR and 1,25-(OH)2D levels in all three diseases, suggesting that in these diseases 1,25-(OH)2D production is regulated in some manner by phosphate transport. Furthermore, previous work indicated that in tumoral calcinosis broad variation exists in serum phosphorus levels. In our patients a negative correlation was found between the serum PTH concentrations and both serum phosphorus levels and TmP/GFR values, respectively. We postulate that although the basic defect in tumoral calcinosis most likely resides in the proximal renal tubular cell, the variation in serum phosphorus levels and possibly disease expression is modulated in part by PTH.

The concurrence of hypoparathyroidism provides new insights to the pathophysiology of X-linked hypophosphatemic rickets.

Controversy exists over the role that PTH and extracellular fluid calcium concentration may play in modulation of the renal phosphate transport defect in X-linked hypophosphatemic rickets. In previous studies, administration of PTH to affected subjects resulted in an increase or no effect on renal phosphate excretion, while calcium infusion increased renal tubular phosphate transport. In contrast, patients with X-linked hypophosphatemic rickets and hyperparathyroidism have no change in their renal phosphate wasting after parathyroidectomy. However, none of these were permanently hypoparathyroid postoperatively. We describe a patient with idiopathic hypoparathyroidism in whom we proved the coexistence of X-linked hypophosphatemic rickets using family history and dental abnormalities. Initially, the patient had a mean serum calcium level of 5.6 +/- 0.07 (+/- SE) mg/dl and a renal tubular maximum for reabsorption of phosphate per liter glomerular filtrate (TmP/GFR) of 6.5 +/- 0.46 mg/dl. Hypoparathyroidism was confirmed, and therapy with vitamin D (50,000 U/day) and calcium (1,000 mg/day) was begun. On this regimen, serum calcium rose to 8.1 +/- 0.2 mg/dl, and TmP/GFR declined to 2.59 +/- 0.12 mg/dl. Bone biopsy revealed the persistence of osteomalacia. Subsequently, therapy with 1,25-dihydroxyvitamin D3 (1.0 microgram/day) was initiated, and serum calcium rose to 9.6 +/- 0.07 mg/dl, and TmP/GFR declined to 1.79 +/- 0.16 mg/dl. The prevailing serum calcium level correlated inversely with the TmP/GFR (r2 = 0.91; P less than 0.001). These data indicate that calcium and/or PTH are involved in modulation of the renal phosphate transport defect in X-linked hypophosphatemic rickets.

Genetic transmission of tumoral calcinosis: autosomal dominant with variable clinical expressivity.

Tumoral calcinosis is a rare inherited metabolic disorder characterized by hyperphosphatemia, elevated serum 1,25-dihydroxyvitamin D levels and periarticular cystic and solid calcifications. Based on previous investigations, the inheritance of this disorder has been postulated to be autosomal recessive. This interpretation was based on finding clinically affected subjects in only single generations of kindreds. We investigated four generations of an affected kindred and found nine subjects with the disease. A unique dental lesion which is specific for this disorder and serves as a phenotypic marker was identified in two generations of the kindred. In all affected subjects, elevated serum 1,25-dihydroxyvitamin D levels were found, although each member did not have the classical clinical findings of tumoral calcinosis. The possibility that this disorder may be variably expressed and have multiple formes frustes has not been previously considered. Using the unique dental lesion as well as the classical clinical and biochemical abnormalities, we found that in this kindred, tumoral calcinosis is transmitted in an autosomal dominant mode, with variable clinical expressivity.

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.

Managing patients with complications of osteoporosis.

This article reviews the impact of osteoporosis on quality of life. It defines specific impairments and suggests how best to minimize the impact of osteoporosis on patients' daily lives. Specific issues such as a spinal deformity, limitations on activities of daily living, pain, functionality, social impairment, self esteem, and depression also are addressed. Finally, a multidisciplinary team approach to osteoporosis is advocated.

Heterogeneity in Paget disease of the bone.

Paget disease of the bone is a common skeletal disorder. Recently, a gene for Paget disease was localized to 18q with subsequent evidence for linkage heterogeneity. We report the identification and clinical characterization of a large pedigree of Paget disease and demonstrate that the Paget disease gene in this pedigree is not linked to the region on 18q, thus confirming linkage heterogeneity.

The metabolic effects of calcium supplementation in the elderly.

Because the value of calcium supplementation in age-related bone loss is controversial, we conducted a study to examine the effects of six months of calcium supplementation on parathyroid hormone (PTH) and other indices of bone metabolism. Calcium carbonate (1.2 grams elemental calcium/day) or placebo was administered for 6 months to a group of 42 healthy, ambulatory men and women with a mean age of 71. Fasting blood samples and 2-hour urine collections were performed at baseline and at 1 and 6 months. The decline in serum PTH levels from baseline in the calcium-supplemented group was significant in comparison with the placebo group changes (for the calcium group: 40.9 pg/mL at baseline to 34.0 pg/mL at 1 month and 33.2 at 6 months). This drop in PTH was associated with a decline in 1,25 OH-Vitamin D levels from a mean of 38.3 pg/mL to 30.4 pg/mL at 1 month and 31.9 at 6 months. During calcium supplementation, no changes were observed in serum bone Gla protein values. A decline in urinary hydroxyproline excretion was observed at 6 months, but this did not reach significant levels. The present study demonstrates suppression of PTH levels with calcium supplementation, an effect which lasts at least 6 months. This change was accompanied by a decrease in serum 1,25 OH-Vitamin D. The lack of significant changes in either serum bone gla protein or urine hydroxyproline excretion fails to support any significant change in bone turnover occurring with this decrease in PTH.

Effects of short-term administration of glucocorticoids on bone metabolism in healthy elderly men.

OBJECTIVE: To determine the effects of short-term glucocorticoid administration in healthy elderly men on bone GLA protein (BGP) levels, as well as levels of calcium, phosphorus, immunoreactive parathyroid hormone (PTH), and alkaline phosphatase. DESIGN: Subjects served as own control before and after prednisone treatment. SETTING: Male subjects were recruited by telephone from the Duke University Aging Center Volunteer Registry and the Department of Veterans Affairs Medical Center Gerofit Program (a supervised exercise program). PARTICIPANTS: Healthy males age greater than 60 years with no history of diabetes mellitus, glucose intolerance, or prior glucocorticoid use. Subjects could not be taking diuretic agents and could not have osteoporosis. The seven subjects mean age +/- std dev was 68.6 +/- 5.3 years. INTERVENTIONS: Prednisone 40 mg orally for 5 days. Fasting serum was obtained at baseline, on days 7 through 11, 13, 15, and 17. Assays of BGP, calcium, phosphorus, PTH, and alkaline phosphatase were performed. MAIN OUTCOME MEASURES: Changes in serum BGP levels was the primary outcome measure. Changes in serum calcium, phosphorus, PTH, and alkaline phosphatase levels were secondary outcome measures. RESULTS: Treatment caused reduction in BGP levels within 24 hours of first dose of prednisone, with levels dropping an average of 78% during the 5 days of treatment (P = 0.004). Within 24 hours of stopping treatment, BGP was no different from baseline. Other variables did not change with treatment. CONCLUSION: Glucocorticoid treatment suppresses BGP production in healthy elderly men in the same fashion as it does in younger healthy men.