Anthony B. Hodsman

Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis

BACKGROUND Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). CONCLUSIONS Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary

See related commentary by Kanis, page [1829][1] Since the publication of the Osteoporosis Canada guidelines in 2002, there has been a paradigm shift in the prevention and treatment of osteoporosis and fractures. [1][2],[2][3] The focus now is on preventing fragility fractures and their negative

INTERMITTENT ETIDRONATE THERAPY TO PREVENT CORTICOSTEROID- INDUCED OSTEOPOROSIS

BACKGROUND AND METHODS Osteoporosis is a recognized complication of corticosteroid therapy. Whether it can be prevented is not known. We conducted a 12-month, randomized, placebo-controlled study of intermittent etidronate (400 mg per day for 14 days) followed by calcium (500 mg per day for 76 days), given for four cycles, in 141 men and women (age, 19 to 87 years) who had recently begun high-dose corticosteroid therapy. The primary outcome measure was the difference in the change in the bone density of the lumbar spine between the groups from base line to week 52. Secondary measures included changes in the bone density of the femoral neck, trochanter, and radius and the rate of new vertebral fractures. RESULTS The mean (+/-SE) bone density of the lumbar spine and trochanter in the etidronate group increased 0.61 +/- 0.54 and 1.46 +/- 0.67 percent, respectively, as compared with decreases of 3.23 +/- 0.60 and 2.74 +/- 0.66 percent, respectively, in the placebo group. The mean differences between the groups after one year were 3.72 +/- 0.88 percentage points for the lumbar spine (P = 0.02) and 4.14 +/- 0.94 percentage points for the trochanter (P = 0.02). The changes in the femoral neck and the radius were not significantly different between the groups. There was an 85 percent reduction in the proportion of postmenopausal woman with new vertebral fractures in the etidronate group as compared with the placebo group (1 of 31 patients vs. 7 of 32 patients, P = 0.05), and the etidronate-treated postmenopausal women also had significantly fewer vertebral fractures per patient (P = 0.04). CONCLUSIONS Intermittent etidronate therapy prevents the loss of vertebral and trochanteric bone in corticosteroid-treated patients.

Effects of a One-Month Treatment With PTH(1-34) on Bone Formation on Cancellous, Endocortical, and Periosteal Surfaces of the Human Ilium

Using bone histomorphometry, we found that a 1‐month treatment with PTH(1–34) [hPTH(1–34)] stimulated new bone formation on cancellous, endocortical, and periosteal bone surfaces. Enhanced bone formation was associated with an increase in osteoblast apoptosis.

Parathyroid hormone restores bone mass and enhances osteoblast insulin-like growth factor I gene expression in ovariectomized rats

In the osteopenic rat model, estrogen deficiency results in increased bone turnover with net bone loss occurring during cancellous modeling. However, estrogen-deficient rats treated with parathyroid hormone (PTH) experience a net gain of bone tissue due to the anabolic effects of PTH. To evaluate the possibility that local insulinlike growth factor I (IGF-I) production modulates the in vivo balance of bone formation and resorption in ovariectomized (OVX) estrogen-deficient rats and in OVX rats treated with PTH, we have studied the expression of IGF-I mRNA in cancellous bone osteoblasts using in situ hybridization techniques. Three-month-old virgin rats were subjected to sham surgery or OVX. Two weeks later, half the OVX rats began treatment with hPTH(1-34), 5 micrograms/100 g body weight, 5 days/week for 4 weeks. All animals were killed at the same time, providing three groups: sham surgery alone; OVX alone; and OVX + PTH. Bone histomorphometry performed in undecalcified sections of tibial metaphysis confirmed that OVX rats had significantly (p < 0.05) increased bone surface formation rates (BFR/BS, micron 3/micron 2/year) with osteopenia while OVX + PTH rats had increased BFR/BS with increased bone volumes compared to sham animals (p < 0.05). Decalcified tissue from all three groups contained immunoreactive IGF-I. Similar tissue sections were hybridized with an 35S-labeled IGF-I antisense riboprobe. Evaluation of the specific signal over cancellous osteoblasts allowed a relative estimate of IGF-I mRNA transcript abundance in the three groups by counting silver grains per osteoblast, corrected for background activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin-D-Resistant Osteomalacia in Hemodialysis Patients Lacking Secondary Hyperparathyroidism

We describe a sporadic, vitamin-D-resistant osteomalacic syndrome in 19 patients undergoing hemodialysis. The syndrome was found in less than 1.5% of patients from referring dialysis centers. All 19 patients had multiple fractures, severe myopathy, and many developed spontaneous hypercalcemia. Severe osteomalacia without evidence of secondary hyperparathyroidism distinguished this syndrome from other forms of renal osteodystrophy. Bone aluminum, measured in six patients, was greatly elevated. Therapy with calcitriol (1 alpha, 25-dihydroxycholecalciferol) lad to clinical improvement in seven patients with reduced pain and myopathy, decreased serum alkaline phosphatase, or both, but no improvement in bone histology. Patients who did not respond clinically to calcitriol developed marked hypercalcemia. The cause of this severe osteomalacia, which occurs despite normal or slightly elevated levels of serum calcium and phosphorus and fails to mineralize with calcitriol, is unclear.

Osteoporosis in men: epidemiology, diagnosis, prevention, and treatment.

BACKGROUND Osteoporosis and fragility fractures in men account for substantial health care expenditures and decreased quality of life. OBJECTIVE This article reviews the most current information about the epidemiology, diagnosis, prevention, and treatment of osteoporosis in men. METHODS Relevant literature was identified through a search of MEDLINE (1966-June 2003) limited to English-language studies in men. The search terms included fractures, bone density, or osteoporosis plus either epidemiology, diagnosis, prevention, control, or therapy. Additional search terms included specific subtopics (eg, bisphosphonates, calcium, exercise, parathyroid hormone). The authors contributed additional relevant publications. RESULTS Morbidity after fragility fracture is at least as high in men as in women, and the rate of fracture-related mortality 1 year hip fracture is approximately double in men compared with women. The bioavailable fraction of testosterone slowly declines into the ninth decade in men. There is evidence that the effect of estrogen on bone is greater than that of testosterone in men. Diagnosing osteoporosis in men is complicated by a lack of consensus on how it should be defined. Significant risk factors for osteoporosis or fracture include low bone mineral density, previous fragility fracture, maternal history of fracture, marked hypogonadism, smoking, heavy alcohol intake or alcoholism, low calcium intake, low body mass or body mass index, low physical activity, use of bone-resorbing medication such as glucocorticoids, and the presence of such conditions as hyperthyroidism, hyperparathyroidism, and hypercalciuria. Prevention is paramount and should begin in childhood. During adulthood, calcium (1000-1500 mg/d), vitamin D (400-800 IU/d), and adequate physical activity play crucial preventive roles. When treatment is indicated, the bisphosphonates are the first choice, whereas there is less support for the use of calcitonin or androgen therapy. Parathyroid hormone (1-34) is a promising anabolic therapy. There is also strong evidence for the use of bisphosphonates for the treatment of glucocorticoid-induced osteoporosis.

Use of FTIR Spectroscopic Imaging to Identify Parameters Associated With Fragility Fracture

BMD does not entirely explain an individuals risk of fracture. The purpose of this study was to assess whether specific differences in spatially resolved bone composition also contribute to fracture risk. These differences were assessed using Fourier transform infrared spectroscopic imaging (FTIRI) and analyzed through multiple logistic regression. Models were constructed to determine whether FTIRI measured parameters describing mineral content, mineral crystal size and perfection, and collagen maturity were associated with fracture. Cortical and cancellous bone were independently evaluated in iliac crest biopsies from 54 women (32 with fractures, 22 without) who had significantly different spine but not hip BMDs and ranged in age from 30 to 83 yr. The parameters that were significantly associated with fracture in the model were cortical and cancellous collagen maturity (increased with increased fracture risk), cortical mineral/matrix ratio (higher with increased fracture risk), and cancellous crystallinity (increased with increased fracture risk). As expected, because of its correlation with cortical but not cancellous bone density, hip BMD was significantly associated with fracture risk in the cortical but not the cancellous model. This research suggests that additional parameters associated with fracture risk should be targeted for therapies for osteoporosis.

Management of corticosteroid-induced osteoporosis.

OBJECTIVES To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. METHODS This review summarizes the pathophysiology of corticosteroid-induced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. RESULTS Despite our lack of understanding about the biological mechanisms leading to corticosteroid-induced bone loss, effective therapy has been developed. Bisphosphonate therapy is beneficial in both the prevention and treatment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroid-induced bone loss and should be administered in combination with other agents. CONCLUSIONS Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroid-induced osteoporosis.

Bone mineral density and the risk of fracture in patients receiving long-term inhaled steroid therapy for asthma

To determine whether high-dose or prolonged inhaled steroid therapy for asthma increases a patients risk of osteoporosis and fracture, we measured bone density in 26 men and 43 women (41 postmenopausal, all of whom had received supplemental estrogen therapy) after treatment with an inhaled steroid for 10.1 +/- 5.5 years and oral prednisone for 10.7 +/- 9.7 years (mean +/- SD). Most had stopped receiving prednisone since commencing the inhaled steroid therapy. We found that bone densities (adjusted for age and sex to yield a z score) were lower in association with higher daily doses of inhaled steroid (p = 0.013 ANCOVA) and with the duration of past prednisone therapy (p = 0.032). Larger cumulative inhaled steroid doses were associated with higher bone densities (p = 0.002) and a reduction in the numbers of patients at risk of fracture. Bone density also increased with the amount of supplemental estrogen therapy (p = 0.058) and, at equivalent levels of inhaled and oral steroid use, women showed higher bone density z scores than did men. Women with a lifetime dose of inhaled steroid greater than 3 gm had normal bone density regardless of the amount of past or current prednisone use or the current dose of inhaled steroid. These data indicate that the daily dose, but not the duration, of inhaled steroid therapy may adversely affect bone density, and that estrogen therapy may offset this bone-depleting effect in postmenopausal women.