Osteoporosis & Rheumatic Disorders
Osteoporosis is a disease characterized by generalized loss of bone mass, which leads to increased risk of fracture. Twenty-eight million Americans have Osteoporosis or are at risk for Osteoporosis. Of the population over 51 years of age, 40% of the women and 13% of the men suffer one or more Osteoporotic fractures during their lifetime, at a cost to the health care system in excess of $13.8 billion per year. The number of elderly people in the population is increasing rapidly, because fractures are associated with increasing age, it is estimated that the number of fractures and associated costs could triple by the year 2040. Strategies to prevent risk of bone loss in patients at risk of Osteoporosis may have substantial impact on reducing the anticipated number of fractures, morbidity, and health care costs.
The skeleton is composed of 20% trabecular bone, which is more metabolically active and is locates in the spine, epiphyses, and pelvis, and 80% of cortical bone, which is concentrated in the appendicular skeleton. Bone mass is normally maintained by the tight coupling of bone resorption by osteoclasts and bone formation by osteoblasts. Peak bone mass is achieved after puberty until the third decade; thereafter, there are age-related decreases in bone mass in both sexes. In women, there is a phase of accelerated bone loss during early menopause; this loss slows after 5 to 8 years. During the course of a lifetime, women lose approximately 50% of the bone in the spine proximal femur and 30% of the bone in the appendicular skeleton; men lose approximately 33% and 20%, respectively. Both loss is therefore a universal component of aging, but this process is now both preventable and treatable. Osteoporosis in patients with rheumatic disease of particular concern because bone loss may result from the disease process and from the medications used to control inflammation. Decreased bone mass, combined with an increased tendency of persons with musculoskeletal disease fall, may also increase the risk of fracture. The chapter focuses (1) on the diagnosis and treatment of Osteoporosis both in general and in patients with systemic rheumatic disorders and (2) on the skeletal effects of corticosteroids and other drugs used to treat rheumatic diseases.
OSTEOPOROTIC RISK FACTORS AND SECONDARY CAUSES OF BONE LOSS AND OSTEOPOROSIS
Peak bone mass accumulation is achieved by the second to third decade, after which several factors influence the rate of bone loss. Risk factors for Osteoporosis include a personal history of a fracture after age 40, first-degree relative with a history of fracture, white or Asian race, cigarette smoking, weight less than 127 pound, height more than 5 feet 7 inches, advanced age, frailty and dementia. Secondary modifiable risk factors included inadequate intake of dietary calcium and vitamin D, low testosterone levels in men, pre-menopausal estrogen deficiency, excessive alcohol intake, impaired vision, neurologic disorders, lack of sunlight, and physical inactivity. There is evidence that genetics are strong determinants of bone mass. Collagen type 1?1 (COL1?1) gene is associated with lower bone density and an increased risk of fracture. There are racial differences in the prevalence of Osteoporosis: 21% of postmenopausal American white women have Osteoporosis, in comparison with 10% of African American women and 16% of Mexican American women.
Although Osteoporosis is a heterogeneous disorder, it develops as a consequence of a net increase in bone resorption with insufficient new bone formation. Secondary causes of Osteoporosis may accelerate bone loss and increase the risk of Osteoporosis with increasing age. Secondary causes include gonadal deficiencies (hypogonadism in men, premenopausal amenorrhea lasting more than 1 year, premature ovarian at less that 45 years of age, and menopause), decreased body mass index and decreased body fat, excessive alcohol intake, cigarette smoking, medical conditions altering bone turnover and medications interfering with bone metabolism.
Causes of Osteoporosis/Osteopenia
Juvenile Osteoporosis, idiopathic Osteoporosis, postmenopausal Osteoporosis, involutional Osteoporosis
Corticosteroid excess, thyrotoxicosis, hypogonadism (causes including anorexia nervosa and prolactinomas), primary hyperparathyroidism, hypercalciuria, vitamin D deficiency
Process affecting the marrow
Multiple myeloma, leukemia, lymphoma, anemias (sickle cell disease, thalassemia minor, Gaucher’s disease, mastocytosis)
Bed rest, space flight
Postgastrecotomy, celiac disease, primary biliary or alcoholic cirrhosis
Anticonvulsants, heparin, methotrexate, corticosteroids, excess thyroid hormone, gonadotopin-releasing hormone agonist, cyclophosphamide, lithium, cyclosporine, aluminum, premenopausal tamoxifen, excessive alcohol
Connective tissue disorders
Osteogenesis imperfecta, scurvy, homocystinuria, Ehlers-Danlos syndrome
Ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus
Modified from leboff MS, Fuleihan El-Hajj C. Brown E: Osteoporosis and Paget’s disease of bone. In Branch WT (ed): Office Practice of Medicine Philadelphia: WB saunders 1994;700.
Hypercortisolism in Cushing’s syndrome often produces Osteoporosis, and administration of exogenous corticosteroids is the most common secondary case of bone loss. Hyperthyroidism increases bone turnover; supraphysiologic doses of thyroid hormone (once the thyroid-stimulating hormone (TSH) level is suppressed) may cause bone loss, even though concentrations of thyroid hormone may be within the normal range Amenorrhea and hypogonadism may result from use of gonadotropin-releasing hormone (GnRH) agonists, hyperprolactinemia, cytotoxic drugs, or anorexia nervosa, and testosterone deficiency in men may be associated with bone loss. Table 40-1 lists other secondary causes Osteopenia and Osteoporosis.
Bone density is the best single predictor of a future fracture risk. The advances in bone densitometry and the development of new techniques such as duel energy x-ray absorptiometry (DEXA) make it possible to rapidly and precisely quantify the amount of bone in the relevant fracture sites in the spine, proximal femur, forearm, and total body with minimal radiation exposure (e.g., 3 to 6 mrad each and 0.5 mrad for total body). The bone mineral density (BMD) in a patient is reported as a standard deviation in comparison with that of (1) young normal controls, to asses whether there is a decrease in BMD from peak bone mass (T score), and (2) age-matched controls, to determine whether the bone density is reduced relative to age-matched controls (Z score). Diagnostic criteria for BMD were established by the World Health Organization (WHO): normal BMD is represented by a T score of between –1 and –2.5; and established osteoporosis is represented by a T score of less than –2.5 and a previous history of a fragility fracture. Prospective studies show that in subjects over 60 years of age, a 1- standard deviation decrement in BMD in comparison with age-adjusted controls is associated with a 1.3 to 2.8 increase in relative risk of fracture. A reduced bone density of the proximal femur is more predictive of increased risk of fracture in the hip than at an alternative site.
The indication for bone densitometry measurements established by the Scientific Advisory Board of the National Board of the National Osteoporosis Foundation are all follows: (1) estrogen deficiency or postmenopausal state in women less than 65 years old with one or more risk factors; (2) age over 65 years old for all women regardless of risk factors; (3) fractures in postmenopausal women; (4) monitoring efficacy of treatment in patients receiving prolonged estrogen replacement or other therapy for osteoporosis; (5) consideration of hormone therapy in women if a BMD would facilitate the decision. These indications are now incorporated into the Health Care Financing Administration policy, which also recommends BMD for (1) all patients with primary or secondary hyperparathyroidism, because a low bone mass identifies patients at risk for osteoporosis, is an indication for parathyroidectomy, or is an indication for therapeutic intervention, and (2) all corticosteroid-treated patients, to determine low bone mass and the need for therapy. In healthy premenopausal women, the use of bone densitometry for screening purposes is not cost effective.
Therapeutic interventions are recommended for prevention of bone loss in patients with osteopenia and for treatment of patients with osteoporosis; these treatment options are discussed in later sections. Studies, however, suggest that changes in BMD may underestimate improvements in bone strength as seen when the mechanical force required to fracture a bone is calculated. Significantly different increases in BMD are seen with alendronate and calcitonin (6% per year vs. 2% to 3% per year) and yet both decrease fracture risk (48% vs. 37%, respectively). Future studies will increase out understanding of fracture prevention and how best to monitor therapy.
OSTEOPOROSIS IN RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is associated with development of periarticular and generalized osteopenia and increased incidence of fractures, which in turn may add substantially to the disability already associated with RA. Gough and associates studied patients who had had RA for less than 2 years and compared them with healthy controls over a 2-year period, monitoring bone density and markers of bone turnover. Patients with early RA lost 3% of lumbar BMD and 5% of femoral neck BMD, in comparison with 1% losses in controls. This finding is in contrast with those previous studies, which showed an increase in bone loss in the distal radius but failed to show accelerated spinal bone loss early in the course of the disease. Investigations with bone densitometry in patients with long-standing RA showed significant decrements in BMD of the proximal femur, the lumbar spine, and the appendicular sites ranging from approximately 5% to 25%. Consistent with these findings is evidence of increased trabecular bone loss in iliac crest biopsies in women with RA. Reported levels of circulating sex corticosteroids in women with RA are conflicting. Demir and colleagues studied patients with active and quiescent RA and found that basal and stimulated levels of cortisol, growth hormone, and adrenocorticotropic hormone (ACTH) were impaired by 65%, 85%, and 30% respectively. Other data showed reduced levels of the major adrenal androgen precursor to estrogen, dehydroepiandrosterone sulfate (DHEAS), in postmenopausal women with RA in comparison with control subjects. This may be a consequence of chronic illness and an alteration in the hypothalamic-pituitary-adrenal axis resulting from suppression of the immune system. These low adrenal androgen levels are of potential importance because, in addition to being precursors of estrone, androgens are protective of bone. Sambrook and coworkers showed a positive correlation between DHEAS levels and longitudinal changes in femoral neck bone density in postmenopausal women with RA.
Physical activity correlates with bone density measurements and is an important determinant of osteoporosis in RA. Patients with severe functional impairment have the lowest forearm bone density. Other factors postulated to contribute to the decreased BMD and osteoporotic fractures in RA include enhanced inflammatory processes with elevated mediators of bone resorption; corticosteroid therapy; and other drug therapy.
RHEUMATOID ARTHRITIS: POTENTIAL MEDIATORS OF BONE LOSS
The release of inflammatory cytokines or other local factors from the macrophages, fibroblasts, and T cells present in rheumatoid synovium may also contribute to the increased bone loss in RA. Synovial biopsies from patients with RA, when cultured with 1,25 (OH) vitamin D, are capable of differentiating to osteoclasts. The following are potential mediators of bone loss in RA: (1) interleukin (IL)-1, IL-6, IL-15, and IL-17; (2) tumor necrosis factor (TNF); (3) heparin; (4) nitric oxide; and (5) prostaglandins. These are significant elevations of IL-1 in the blood and synovial fluid in patients with RA, which stimulates osteoclast formation, activation, and bone resoprtion. Elevations of TNF-α in the blood and synovial fluid and high concentrations of IL-6 in the synovium, both of which can increase bone resorption and stimulate osteoclast formation, may also contribute to the development of osteoporosis in the patients with RA. Studies have shown that IL-15 and IL-17 appear to induce osteoclastic maturation, which may be a crucial step in RA-induced bone resorption. In addition, release of mast cell mechanisms underlying the effects of heparin on skeletal metabolism have not been fully elucidated, although heparin promotes parathyroid hormone (PTH)-mediated bone loss and may increase bone collagen metabolism. Nitric oxide and prostaglandins, regulated by cytokines such as IL-1 and TNF-α , are produced in the rheumatoid synovium, and high concentrations of prostaglandins, particularly prostaglandin E2 (PGE2), enhance bone resorption.
BONE METABOLISM IN RHEUMATOID ARTHRITIS
To assess whether the skeletal changes in patients with RA represent more generalized abnormalities in mineral metabolism, investigators have examined indices of skeletal homeostasis. Normally, there is an inverse relationship between changes in calcium concentrations and PTH secretion, so that a small decrease in the ionized calcium concentration augments PTH release, with secondary renal conservation of calcium, mobilization of calcium from bone, and activation of 25-hydroxyviatamin D to 1,25-dihydroxyvitamin D, which in turn stimulates intestinal calcium absorption. The reduced serum calcium levels in patients with RA reported in early studies probably represent decreased calcium-binding proteins from chronic disease and not a reduction in ionized calcium concentrations, although the latter were not measured. Moreover, in patients with RA, levels of PTH and vitamin D metabolites are generally similar to those in controls, thus indicating no abnormality in calcium metabolism.
Studies if markers of bone turnover confirm the results of the vivo and in vitro studies described earlier. Gough and associates studied patients with RA for less than 2 years. In addition to the bone losses described earlier, the markers of the bone formation, osteocalcin and alkaline phosphatase, are reduced in early disease but do not correlate well with disease activity or changes in bone density. Gough and associates found that urinary pyridinoline and deoxypyridinoline concentrations, the markers of bone resorption and changes in bone density. This suggests that the degree of systematic and local inflammation may control bone loss.
RHEUMATOID ARTHRITIS AND CORTICOSTEROIDS
Early studies of patients with RA indicated accelerated bone loss caused by corticosteroid administration. Corticosteroids are associated with an increased risk of osteoporosis. Consistent with theses deleterious effects of corticosteroids on bone are the observations of Dykman and associates, who showed large cumulative doses of corticosteroids in patients with rheumatic diseases increased both trabecular bone loss in the forearm and the risk of skeletal fractures. Als and colleagues observed decreased bone density in corticosteroid-treated premenopausal women with RA, which correlated with the duration of therapy and the cumulative dose. A randomized controlled trial by Laan and coworkers showed early bone loss in the spine in a group of rheumatoid patients treated for up to 20 weeks with prednisone (mean dose, 7.5 mg/day), which was partially reversible with corticosteroids undergo an early reduction in bone density, patients receiving long-term corticosteroid therapy have less bone loss than do patients treated with calcium supplements or anti-inflammatory drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), penicillamine, and gold.
A large cross-sectional study of 195 patients with rheumatoid arthritis suggests that bone loss in patients with RA is more evident in the proximal femur than in the spine. Both cumulative corticosteroid dose and disability correlate significantly with bone density. In patients who had discontinued corticosteroid therapy, however, bone densities were similar to those of patients who had never used corticosteroids. Other data indicate that postmenopausal women with RA who take long-term, low-dose corticosteroids or groups of premenopausal and postmenopausal women taking low doses of prednisone do not have an additional decrease in bone density in comparison with non-corticosteroid-treated subjects with RA. The lack of an adverse effect of low-dose corticosteroids on bone mass in postmenopausal women with RA probably results from suppression of the active inflammatory process and of cytokines and/or from improved function and increased physical activity. Corticosteroids may therefore produce an early loss of bone, but this bone loss may be attenuated over time by better control of the disease process, increased ambulation, and physical activity.
CORTICOSTEROIDS AND OSTEOPOROSIS
Glucocorticoids have been known for many years to cause osteoporosis. Steroids are a necessary mainstay of therapy for many medical conditions, including RA, polymyalgia rheumatica, giant cell arteritis, connective tissue disease (systematic lupus erythematosus, mixed connective tissue disease, polymyositis, and overlap syndromes), and vasculitis. Osteoporotic fractures or osteonecrosis occurs in up to 50% of patients treated with long-term glucocorticoids. The risk of bone loss or associated fracture risk is determined by cumulative corticosteroid dose, increasing age, and/or menopausal status.
Steroids primarily cause a decrease in bone formation. The mechanism appears to be a decrease in osteoblast activity, resulting in a decrease in osteoblast function and premature apoptosis. Impaired osteoblast function is manifested as an initial induction of osteoblast differentiation, followed by decreased synthesis of both type I collagen and osteocalcin and decreased osteocalcin levels in a dose-dependent relationship, thereby causing bone loss. The production of osteoclasts is also decreased, leading to a decrease in bone turnover. The result is weakened bone matrix with thin, bony trabeculae that contributes to osteoporosis.
Treatment of patients with more than 15 mg of prednisone per day impairs intestinal calcium absorption and increases urinary calcium excretion. These mechanisms appear to play an important role in the development of secondary hyperparathyroidism. Although in vitro studies have shown both stimulation and inhibition of bone resorption after corticosteroids do not display enhanced bone loss, which suggests that PTH may mediate the bone resorption in this setting. PTH increases the resorption of bone directly and also increases the number of site at which bone remodeling occurs. Lower doses of prednisone (range, 2.5 to 10 mg/day) in patients with RA do not affect PTH levels, as measured by the immunoradiometric assay for intact hormone. Also, alternate-day glucocorticoid regimens may maintain intestinal calcium absorption and prevent elevations of PTH but do not prevent bone loss in adults. Earlier studies indicated that corticosteroids interfere with the activation of vitamin D to 25-hydroxyvitamin D as well as to 1,25-dihydroxyvitamin D, but more recent data show that corticosteroids do not interfere calcium transport mechanisms in the bowel mucosa by reducing levels of vitamin D receptors and possibly inhibiting protein synthesis.
Corticosteroid therapy causes hypogonadism, which may further contribute to bone loss. Corticosteroids inhibit pituitary secretion of gonadotropins and also directly decrease gonadal production of estrogen and testosterone. Steroid therapy reduces circulating free testosterone and a 40% decrease in free testosterone. Steroids also reduce endogenous ACTH levels and adrenal androgen production of androstenedione and DHEAS. Decreases in sex hormones exacerbate the bone loss by increasing osteoclast-midiated bone resorption. Glucocorticoid- induced myopathy and muscle weakness also contribute to bone loss by removing the forces on bone prduces by muscle contraction.
The phase of the most rapid glucocorticoid-induced bone loss occurs within the first 6 months of therapy, with losses of 3% to 15% in the lumbar spine at 1 year. In a meta-analysis of two randomized controlled trials in early RA, Verhoeven and Boers showed that patients with RA treated with 1 to 10 mg of corticosteroid per day had no change in the lumbar spine and 3.0% decrease in hip bone density; patients with RA not treated with steroids had a 0.6% decrease in bone density at the spine and a 0.7% decrease at the hip. However, Verhoeven and Boers also showed that patients with RA who took steroids had a 4.7% bone loss at the spine and a 1.5% at the hip. Patients with nonrheumatologic diseases may lose up to 5% of bone mass per year; this loss occurs mostly in the first 6 moths of therapy.
Corticosteroid use is associated with increased fractures of the predominantly trabecular bones, vertebrae, femoral head, distal radius, and ribs. In postmenopausal women more than 65 years old, a decrease of bone density by 1 standard deviation doubles the risk of spinal fractures. However, gluocorticoid-treated patients appear to suffer fractures more easily with a higher bone density. The dosage of corticosteroid therapy influences the fracture risk. According to the preliminary data from Van Staa and colleagues, an average daily prednisone dose of 2.5 to 7.5 mg is associated with a hip fracture risk of 1.77, and more than 7.5 mg/day, with a fracture risk of 2.27. The risk of vertebral fracture is also higher with prednisone: 2.5 mg/day is associated with a risk of 1.55; 2.5 to 7.5 mg/day, with the risk of 2.5; and more than 7.5 mg/day, with a risk of 5.18. According to this study, the risk of fracture declined to baseline one steroid therapy was discontinued. Physicians are now more aware that glucocorticoids induce osteroporosis and increase the risk of fracture. Concern regarding bone loss remains a limiting factor in making treatment decisions regarding the dosage and duration of corticosteroid therapy. Corticosteroid-induced osteoporosis is therefore likely to continue to be a problem in the future.
DRUG THERAPIES AND OSTEOPOROSIS
Other drugs used to treat RA may also have an effect on bone mineral metabolism. NSAIDs, gold, and penicillamine do not appear to prevent osteopenia in RA, although the effects nonsteroidal drugs on bone loss are conflicting. It is possible that some NSAIDs that inhibit prostaglandin synthesis may play a role in retarding the progressive bone loss in patients with high endogenous prostaglandin production, such as occurs in RA. In vitro studies show that gold salts inhabit bovine osteoclast activity, and this may account for some of their beneficial effects in inhibiting disease activity in RA. Methotrexate in high doses used to treat childhood leukemia is associated with osteoporotic fractures. In vitro studies show that methotrexate inhibits osteoclast proliferation but not differentiation. In a prospective, randomized, placebo-controlled study, low doses of methotrexate used for the treatment of RA. Cyclosporine produces time-and dose-dependent bone loss in rodent models, and therapy with both cyclosporine and prednisone is associated with osteoporosis inherent transplant recipients, which raises the possibility that use of this drug in patients with RA may accelerate the development of osteoporosis. Alternative agents, such as azathioprine or cyclophosphamide, do not produce osteoporosis, but these agents are associated with an increased risk of cancer. Cyclophosphamide may cause premature ovarian failure, resulting in phase of rapid bone loss.
Appropriate interventions for the treatment of rheumatologic diseases must have an effect on disease activity. Complications that result from therapy must be considered early, and alternative treatments or preventive strategies should be considered whenever possible.
BONE LOSS IN SYSTEMIC LUPUS ERYTHEMATOSUS
The importance of bone loss in patients with systemic lupus erythematosus (SLE), as in RA cannot be over-emphasized. Disease activity is associated with the elevated numbers of cytokins, such as interleukins and TNF, which directly affect bone metabolism, as discussed earlier. Young women are the people most susceptible to SLE, often have associated renal disease and/or premature ovarian failure as a result of immunosuppressive or alkylating therapy, and are frequently treated with high doses of prednisone for prolonged periods of time. On the basis of studies of patients with cancer, daily oral cyclophosphamide for 6 to 48 months is associated with the development of amenorrhea in 50% to 70% of women treated. Regimens that involve pulse cyclophosphamide for shorter periods of time may minimize the risk of ovarian toxicity. Studies have shown that SLE is associated with a loss of trabecular bone. Teichmann and associates showed that female patients with newly diagnosed SLE lose bone at the same rate as do women with longstanding SLE, and the reduction in BMD correlates with the excretion of urine hydroxyprolinhe, with hypocalcemia, and with a decrease in osteocalcin. In a cohort of women with SLE, 42% of the women had T scores of less than –1 at the spine and 44% at the hip; 13%4 of the women had T scores of less than –2.5 at the spine and; 6.3%at the hip. Previous use of steroids was strongly inversely related to BMD at the spine, but not as strongly at the hip. There is a risk of lupus flares during pregnancy, and some investigators have therefore raised concerns about instituting hormone replacement therapy in postmenoausal women. The benefits of postmenopausal hormone replacement therapy are clear, and retrospective studies have suggested that hormone replacement therapy may be well tolerated in women with inactive or mild stable SLE. A large, prospective, double-blind, placebo-controlled study, inclusive of all ethnic groups, the Safety of Estrogens in Lupus Erythematosus – National Assessment (SELENA) trial, should provide the basis for definitive recommendations in the near future.
BONE LOSS IN OSTEOARTHRITIS
Osteoarthritis (OA) is the most common musculoskeletal disorder treated by the rheumatologist. The primary disorder of chondrocyte function results in secondary changes in bone. Bone biopsies from patients with seer OA show a significant increase in trabecular thickness and separation, with a decrease in trabecular number. THe osteophyte formation in OA may factitiously elevate bone density measurements of the spine without affecting the proximal femur sites; this makes it difficult to assess bone density in the lumber spine. Cautious interpretation of DEXA of the lumbar spine is essential to ensure that osteophytes do not falsely raise the spinal bone density reading. Osteophytes are seen in the lumber spine in up to 75% of men and 61% of women over the age of 60 years, with 31% and 27%, respectively, at the hip. Hannan and coworkers demonstrated that proximal femur bone density was higher in women with mild OA of the knee than is subjects with no OA, although patients with advanced OA of the knee had bone density similar to that of control subjects. Moderate to severe OA is associated with increased appendicular and axial BMD. The association of increased body weight with OA may partly explain this higher bone mass. Degenerative arthritis of the axial skeleton and lower extremeties results in decreased levels of function that may accelerate bone loss. Patients with OA may develop age-related bone loss, and the common co-occurrence of these two age-related disorders should be considered in managing these patients.
BONE LOSS IS POLYMYALGIA RHEUMATICA
(Osteopenia in patients with polymyalgia rheumatica (PMR) is not generally found to be a problem, although the bone loss has not been widely studied. Persons with PMR are generally physically active soon after initiation of treatment. Although some patients with PMR may have associated low-grade peripheral synovitis, they lack significant joint involvement and are likely to participate in day-to-day weight-bearing activities. The initial dose of prednisone used to treat patients with PMR and the duration of therapy are widely variable. Clinicians frequently initiate therapy with NSAIDs before prednisone; this may facilitate a shorter duration of treatment with prednisone. Symptoms are occasionally controlled without corticosteroids. In some instances, prolonged intermediate doses of prednisone are required, and significant bone loss may be expected. Pearce and colleagues studied 19 patients with PMR who took 2.5 to 10 mg of prednisone daily for a 14-month period. Markers of bone turnover showed a dose-related reduction in osteocalcin, which returned to normal at dosages of less than 5 mg/day; urine resorption markers were 57% higher than those of controls and decreased by 27% within 1 month of treatment; and muscle strength increased by 20% to 60%. Despite diseased remission, bone density decreased by 2.6% at the spine and by 2.9% at the hip; in the first 6 months, spine BMD decreased b 1.7% and after 6 months, BMD decreased by 8.5% at Ward’s triangle and by 4.8% at the femoral neck. The decreases in BMD correlated with the cumulative dose of prednisone. Lower doses of prednisone may be bone sparing, but the underlying disease may not be controlled.
BONE LOSS IN ANKYLOSING SPONDYLITIS
Ankylosing spondylitis is also associated with the development of osteoporosis. Typically, patients with ankylosing spondylitis have symptoms, starting in the teenage years, that consist of persistent low back pain and morning stiffness. Eventually, the inflammatory symptoms and pain may subside, but patients have residual decreased range of motion in the axial skeleton and are less active. This disorder is often associated with peripheral arthritis, particularly of the large joints of the lower extremities, including the hips; therefore, there may be further decrease in weight-bearing activity. Eventually, total joint arthroplasty may further limit physical activity and weight-bearing exercises.
Lee and associates showed in men with ankylosing spondylitis that bone density is lower in the spine and hip and that this loss is more marked with later disease. No abnormal parameters of bone metabolism were identified, but bone biopsy revealed a reduced bone volume and trabecular width. Evaluation of testicular function inn 22 males with ankylosing spondylitis showed increased luteinizing hormone levels and deficient testicular reserve, which may contribute to the development of osteoporosis. However, other investigators have shown no evidence of hypogonadism in males with ankylosing spondylitis. An atypical osteomalacia diagnosed according to histologic criteria has also been documented in four men with ankylosing spondylitis spondylitis who had no alterations in calcium or PTH levels.
In patients with chronic ankylosing spondylitis, the most significant complication of concern is spinal fracture. The fracture potential increases in the cervical, thoracic, and lumbar regions because of the ankylosed spine. Minor trauma is the most common cause of fracture in these persons. Serious complications include complete and incomplete spinal cord lesions and development of other associated neurologic deficits. Radiographic visualizations of the fracture site may be difficult because of the extensive syndesmophyte formation. The use of a radionuclide bone scan or a computed tomographic (CT) scan may help visualize the fracture radiographically. The relationship between osteopenia and he risk of fracture is not fully understood. Donnelly and coworkers examined the relationship between BMD and severity of disease higher rate of fracture and they also found that there was no significant reduction in lumber spine or hip BMD by DEXA in the patient with fracture. Patients with early disease had significantly lower spinal BMD, but BMD increased with advanced disease. At the hip, BMD was lower in patients with more severe disease. Quantitative CT may be more useful than DEXA in determining the degree of the extensive paraverebral syndesmophyte formation. Nevertheless, active intervention with agents that reduce one loss should be considered for these patients.
EVALUATION OF A PATIENT WITH BONE LOSS OR OSTEOPOROSIS
The evaluation of a patient at a risk for osteoporosis must include screening for secondary causes of bone loss, as outlined in Table 40-1. A complete history, physical examination ad laboratory evaluation are essential (Table 40-2). Laboratory tests include the measurement of serum electrolytes, calcium, phosphorus and alkaline phosphate levels; liver tests; a complete blood cell count; measurement of erythrocyte sedimentation rate; serum and possibly urinary protein electrophoresis; measurement of erythrocyte sedimentation rte; serum and possibly urinary protein electrophresis; measurement of a sensitive TSH level and of 25 (OH) vitamin D, urinary calcium, and creatinine levels; and, in some instances, tests of gonadal function and serum PTH concentrations. Markers of bone turnover, urinary N-telopeptides, may be helpful in determining whether this is a state of high or low bone turnover; these are measured in a second morning urine sample. Additional specific tests to rule out endocrinologic or neoplastic processes and a possible bone biopsy (after a double tetracycline label) should be considered in patients in whom there is a question of osteomalacia without biochemical changes to support the diagnosis. Candidates for a bone biopsy include patients with severe bone loss and those in whom primary osteoporosis is uncommon, such as children, pre-menopausal women, men less than 60 years of age, and black persons. All secondary causes of bone loss should be corrected before specific, therapeutic interventions for osteoporosis are considered, because substantial improvements in bone mass may be achieved.
STRATEGIES FOR THE PREVENTION AND TREATMENT OF OSTEOPOROSIS
The goals of therapy for osteoporosis include the reduction of risk factors for bone loss, avoidance of prolonged immobilization, conservative management of pain, and an attempt to halt the disease progression by decreasing bone resorption and increasing bone formation. A regular weight-bearing program that includes endurance, resistance exercises, or both may produce a modest increase in bon mass.
Adequate calcium is necessary for preventing calcium mobilization from the skeleton to maintain blood calcium levels. Studies have yielded widely varying results of the effect of calcium depends on the years since menopause, customary calcium intake, age, and vitamin D status. Prospective studies demonstrate that calcium supplementation is ineffective or minimally effective in preventing bone loss in women within 5 years of menopause, which is the period when estrogen deficiency has a predominant influence on bone loss. Supplemental calcium is beneficial for late-postmenopausal women with low calcium intake (<400 mg/day) and vitamin D deficiency and may prevent up to 2.5% bone loss and decrease the risk of hip fracture by up to 30%. In prepubertal children, calcium intake of approximately 1600 mg/day increases bone density at different sites approximately 3% to 5%, which may ultimately confer an increased peak bone mass.
The national Academy of Sciences devised guidelines for adequate daily calcium intake for all ages in the population: To prevent negative calcium balance, children require 500 to 800 mg; men and premenopausal women require 1000 mg; pregnant and lactating women require 1500 mg; and men over 50 years of age and postmenopausal women require 1200 mg of elemental calcium per day. These levels of calcium intake are generally safe, unless a patient has an underlying disorder of calcium-supplemented orange juice contains approximately 300 mg of elemental calcium. Calcium carbonate, the most widely used calcium salt, contains 40% of elemental calcium/ Each tablet of Tums E-X, for example, contains 300 mg of elemental calcium and Os-Cal 500 and Tums 500 tablets each have 500 mg of elemental calcium. Calcium carbonate should be taken with food because patients with achlorhydria are unable to absorb this calcium carbonate include constipation. Calcium citrate contains 24% elemental calcium, this calcium salt is a more bioavaliable calcium preparation than is calcium carbonate, and it may be taken during fasting.
VITAMEN D: MAINTENANCE AND THERAPY
Low dietary intake of vitamin D and inadequate sunlight exposure result in vitamin D deficiency, secondary hyperparathyroidism, and osteomalacia. A study of patients with Acute hip fractures showed that 50% of the patients had vitamin D deficiency. Vitamin D (700 IU/day) and calcium carbonate (500 mg/day) reduce bone loss and decrease the incidence of non-vertebral fractures by 50%. In elderly nursing home residents with low or low-normal vitamin D levels, vitamin D (800 IU/day) with calcium (1.2 g/day) decreased hip fractures by 43%. Thus, in the elderly, treatment interventions may have a major impact in reducing fractures. Vitamin D deficiency is defined as 25(OH) vitamin D levels of less that 12 to 15 ng/mL; however, PTH level rise at 25 (OH) vitamin D levels ranging from less than 25 to 30 ng/mL. Replacement with vitamin D to his level may therefore prevent PTH-mediated bone loss. Vitamin D at 400 to 800 IU/day is usually adequate for replacement, but higher dose preparations are available, such as vitamin D, 50,000-IU tablet, or Drisdol Drops (vitamin D) 200 IU/drop.
Use of 1,25(OH)2 vitamin D may enhance calcium absorption and bone formation (at pharmacologic dosages; e.g., 0.5 µg/day). Although some studies show that the administration of 1,25(OH)2 vitamin D for osteoporosis is ineffective in maintaining bone mass, high doses of 1,25(OH)2 vitamin D produced some increase in bone density. A reduction fractures in some studies 1,25(OH)2 vitamin d therapy may result from reversal of mild vitamin D deficiency. 1,25(OH)2 Vitamin D has a narrow margin of safety, with potential risks of hypercalcemia and hypercalciuria. In the absence of Vitamin D insufficiency, however most treatment regimens should ensure adequate intake with physiologic doses of vitamin D (400 to 800 IU/day).
Estrogen therapy in postmenopausal women prevents bone loss and decreases the risk of fracture by 50%, possibly though direct interaction with estrogen receptors on bone cell or though reduction in cytokines that stimulate bone resorption (e.g. IL-1, IL-6). In women with no contraindications to its use, hormone replacement therapy is the treatment of choice for preventing and treating osteoporosis. Estrogen decreases the bone loss regardless of whether it is started at the onset of menopause or later in life when considerable bone loss has occurred. Estrogen replacement therapy should be continues for 10 years or more to reduce he risk of hip fractures in older women. Rapid bone loss does occur once estrogen is discontinued, and data show that even after 1 to 2 years of continuous estrogen therapy, bone loss may still occur.
According to data from several observational studies, estrogen therapy reduces the risk of cardiovascular disease, the leading cause of death in postmenopausal women, by approximately 50%. Improved lipoprotein profile, a decrease in total and low-density lipoprotein (LDL) cholesterol, and other mechanisms, such as direct vascular antioxidant effects, mediate the cardioprotective effect of estrogens. However, the Heart and Estrogen/Progestin Replacement Study of the secondary prevention of heart disease in postmenopausal women showed and early increase in the risk of cardiac events, possibly as a result of increased thrombosis associated with oral estrogen therapy. Thus, this study showed no overall protective benefit conferred by the use of hormone replacement therapy in women with established heart disease.
Estrogen is administered in a sequential or continuous regimen with a progestin to diminish the risk of endometrial hyperplasia or carcinoma. Oral estrogen/progesterone regimens often used include (1) 0.625/mg of conjugated estrogen daily, with 10mg of medroxyprogeserone added on days 1 to 14 of each month in a sequential regimen, and (2) 0.625 mg of conjugated estrogen daily, with 2.5 or 5 mg of medroxyprogesterone in a daily continuous hormone replacement regimen. Unlike the sequential hormone replacement regimen, which usually produces regular monthly withdrawal bleeding, daily continuous hormone replacement induces atrophy of the endometrium so that 80% or more of women are amenorrheic at 1 year. In the first 6 months of this latter regimen, 45% of women may experience irregular bleeding. According to the guidelines of the American College of Obstetrics and Gynecology, endometrial biopsies are not routinely necessary unless a woman has irregular bleeding while using hormone therapy. In women who have had a hysterectomy, estrogen is administered alone. Because of the possibility of a slight increase in the risk of breast cancer with estrogen use, regular breast examinations and annual mammography should be performed according o the guidelines of the American Caner Society. Contraindications to estrogen therapy are breast or endometrial cancer and active thrombotic or liver disease (see other guidelines in reference 103). Transdermal estrogens, which, unlike oral estrogens, do not affect serum-binding proteins or clotting factors, also prevent bone loss but produce less beneficial effects on lipoproteins.
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs), a class of nonsteroidal drugs approved by the US Food and Drug Administration (FDA) for the prevention of osteoporosis, have been used in the treatment of breast cancer for many years; an example of these drugs is tamoxifen. They bind to estrogen responsive tissues and act selectively as agonists or antagonists. Previous studies in postmenopausal patients with breast cancer show that tamoxifen has estrogen agonist-like-effects on clotting factors, on the endometrium, and on the bone, preventing bone loss and reducing the risk of spinal fracture by up to 45%. Raloxifene (Evista) is the FDA-approved SERM for the prevention of osteoporosis; it has antagonistic effects to estrogen in the endomerium and breast, decreasing the risk of breast caner by 76% in women treated for osteoporosis, and it has an estrogen-like effect on the lipid profile, decreasing LDL cholesterol 12% and increasing HDL2 cholesterol 15%. Over 2 years in the Multiple Outcomes of Raloxifene trial, raloxifene 60 mg/day, has been shown to increase bone density by 2% per year and to decrease vertebral fractures. The side effects of raloxifene include an increase in deep venous thrombosis, hot flashes leg cramps, and vaginal dryness. At present, raloxifene is approved for the prevention of osteoporosis in patients with osteoporosis and is also approved for the treatment of osteoporosis.
Calcitonin is a 32-amino acid peptide produced by the parafollicular cells of the thyroid, which inhibits bone resorption through its direct effects on osteoclasts that have high-affinity calcitonin receptors. Intranasal calcitonin is approved by the FDA for the treatment of osteoporosis in a dosage of 200 IU/day and should be administered with calcium, 1 g/day, and Vitamin D, 400 IU/day. Adverse effects of calcitonin include nausea in approximately 10% to 15% of patients, flushing, inflammation at the injection site, and rhinorrhea (nasal calcitonin). There may also be beneficial analgesic effect in the presence of vertebral fractures. There may be a plateau of the effect on bone turnover after 1 to 26 months of therapy (tachyphylaxis), possibly a result of refilling in remodeling space and/or down-regulation of calcitonin receptors. Studies in postmenopausal women with osteoporosis show that use of a calcitonin nasal spray (200 IU/day) for 12 months prevents bone loss in the spine and forearm. The prevention Recurrence of Osteoporotic Fractures (PROOF) study, a 3-years, randomized, placebo-controlled study of nasal calcitonin, 200 IU/day, versus placebo in postmenopausal women with established osteoporosis, demonstrated a 37% reduction in the risk of new vertebral fractures regardless of pretreatment characteristics.
Bisphosphonates are pyrophosphate analogs that are absorbed into the hydroxyapatite, crystals of bone and inhibit bone resorption in interfering with osteoclast activity and inducing apoptosis, thereby reducing the depth of the osteoclast resorption cavity and preserving bone structure. Bisphophonates have a sustained effect because of their long half-life in bone. Etidronate, administered intermittently to older osteoporotic women over a period of 2 years, produced a 5% increase in spinal bone density and a 50% reduction in vertebral fractures that was not sustained at 3 years. Etidronate is approved for the treatment of Pagets’s disease of bone but not for the treatment of osteoporosis.
Alendronate (Foxamax) is approved by the FDA for the prevention and treatment of osteoporosis. This is a more potent second-generation biophosphate. Prevention of bone loss in women with osteopenia who took alendronate, 5 mg/day for 2 years, increased bone density of the spine by 2.9% and hip by 1.3%. In women with osteoporosis with a previous fracture, alendronate, 10 mg/day, increased bone density by 7% at the spine and 6% at the femoral neck. The incidence of vertebral fractures was reduced by 50% in women with osteoporosis. However, the Fracture Intervention Study showed that patients with a T score higher than –2 and no previous fracture had no reduction in risk of fracture. Biophosphates are poorly absorbed (<1%), and so they should be taken on an empty stomach with 8 ounces of water at least 30 minutes before meals. No calcium supplements should be taken within 2 to 4 hours of a dose, because calcium binds to alendronate and may impair absorption. Abdominal pain, constipation, diarrhea, flatulence, musculoskeletal pain, and headache may occur more frequently than experienced in the placebo group. Patients with esophageal abnormalities (stricture or achalasia), inability to stand upright for 30 minutes, or hypocalcemia are advised not to use this medication. Preexisting gastro-esophageal reflux-type symptoms may be made worse by alendronate, and in rate cases, esophagitis, ulceration, and erosions occur. To prevent the risk of reflux esophagitis, patients are advised to remain upright for at least 30 minutes after taking the medication.
Alendronate has been used to treat patients with osteoporosis in combination with estrogen replacement therapy, because these medications have different mechanisms of action. Combination therapy results in an additional 2.5 to 3.5% increase in bone density. More potent third-generation biophosphate are being studied in the treatment of osteoporosis. Risedronate (Actonel) is approved for the treatment of Paget’s disease of bone and has recently been approved for the prevention and treatment osteoporosis and the treatment of glucocorticoid-induced osteoporosis. Data have shown that 2 years of treatment with risedronate, 5 mg/day, in postmenopausal women with two or more spinal fractures increases spinal bone density by 7% and are reduced by 40% to 50%, and nonvertebral fractures are reduced by 33% to 39%. Adverse effects were similar in both placebo and treatment groups and no increase in gastrointestinal symptoms was observed.
Sodium fluoride stimulates bone formation and produces large increments in BMD. Adverse effects pf fluoride occur in up to approximately 40% of subjects and include gastrointestinal irritation and a lower extremity pain syndrome with stress fractures. A slow-release fluoride preparation has fewer adverse effects. In prospective, controlled studies of high doses of sodium fluoride for the treatment of osteoporosis (75 mg/day), there was no significant decrease in vertebral fractures, and nonvertebral fractures increased despite an increase in bone density. Use of a slow release fluoride preparation is associated with a 5% increase in spice bone density, a 2.3 increase in femoral neck bone density, significant reduction in vertebral fractures, and fewer adverse effects. Meunier and colleagues performed a 2-year multi-center, prospective, randomized, double blind study of postmenopausal women prevalent vertebral. Subjects were treated with sodium fluoride, 50 mg/day; monofluorophosphate, 150 to 200 mg/day; or placebo (all patients received 1 g of calcium and 800 IU of vitamin D daily.) Despite a 10.8% increase in spine bone density in all fluoride-treated subjects, in comparison with a 2.4% increase in subjects who received calcium and vitamin D alone, there was no prevention of new vertebral fractures. At present the use of fluoride therapy should be restricted to investigate protocols.
Low doses of parental PTH (PTH 1-34, the active amino terminus) given with calcitriol increased trabecular bone in the spine, but it may cause small losses of cortical bone. Studies have shown that postmenopausal women taking estrogen replacement therapy, calcium and vitamin D, when treated with PTH 1-34 for 2 years, have a 13% increase in spinal bone density and an 8% increase of hip bone density with no significant decrease in forearm density. No fracture prevention data are available yet. PTH is not yet recommended for use beyond research protocols, particularly inasmuch as some studies have been stopped because of concerns of bone caners that occur in animal models.
PTH-related protein is now being studied as a potential anabolic agent in postmenopausal women, and results are promising, showing a decrease in markers of bone resorption and an increase in markers of bone formation, which suggest an increase in bone formation. Future directions in the treatment of osteoporosis may include use of anabolic growth factors or other approaches that may stimulate bone formation, but currently there are not yet available.
Because existing therapeutic interventions for established osteoporosis only partially reverse bone loss, preventive strategies to optimize skeletal mass-such as reduction of risk factors for bone loss (according to bone density criteria), adequate calcium and vitamin D nutrition, and a regular weight-bearing exercise program-are important. It is imperative to identify and treat underlying secondary cause of osteoporosis.
Summary of the Treatment of Osteoporosis
Our approach to the treatment of postmenopausal women with osteoporosis is to use hormone replacement therapy as the first-line therapy because of the combined benefit of reducing the risk of cardiovascular disease and osteoporosis. The ongoing prospective randomized Women’s Health Initiative will asses the effects of combined daily continuous estrogen and progesterone therapy on cardiovascular disease, fractures, and breast and uterine cancers. Physicians should therefore cautiously evaluate risk/benefit ratio for hormone replacement therapy is, however, only about 30%, and at present there is no widespread acceptance of this mode of therapy in postmenopausal women. Other strategies at present to prevent osteoporosis include alendronate, 5 mg/day, or raloxifene, 60 mg/day. FDA approved therapeutic strategies to treat osteoporosis include the use of estrogen, with or without progesterone replacement therapy; intranasal calcitonin, 200 IU/day; and alendronate, 10 mg/day.
Because of the concerns about the long retention time of biophosphonates in bone, we are cautious about administering their drugs to the premenopausal women. We also withhold these agents from patients with vitamin D insufficiency until this corrected. The availability of bone densitometry makes it feasible to ensure a therapeutic response to these treatment strategies. Patients who do not maintain or increase bone mass appropriately may require alternative therapeutic approaches. More potent future therapies may help prevent bone resorption and potentially promote bone formation, but further studies are awaited.
STRATEGIES TO PREVENT OR TREAT
CORTICOSTEROID-INDUCED BONE LOSS
Chronic corticosteroid use may cause about 5% to 20% bone loss over 1 to 2 years, with osteoporosis as well-documented sequela. Fracture risk is associated with the dosage of steroid therapy, and discontinuation of steroids may reverse the bone loss in some instances. Strategies to prevent bone loss in all patients should therefore include use of the lowest steroid dosage possible and an evaluation for patients at risk of osteoporosis who may require prophylactic therapy. Initial evaluation should identify the patient at risk for osteoporosis, as previously discussed. Additional risk factors include increases risk of fall as a result of steroid-induced myopathy and muscle wasting; cataracts; and altered mental status. Cooper and associates showed that functional impairment increases the risk of hip fracture among patients with RA, independently of steroid use. Lifestyle modifications may be necessary, but they may not alter the rate of bone loss once corticosteroid treatment begins. An initial biochemical evaluation should include complete blood cell count; measurement of serum electrolytes, creatinine, calcium, alkaline phosphate, phosphorous, albumin, liver enzymes, 25 hydroxyvitamin D, and TSH; possibly a measurement of free testosterone in males; and a 24-hour measurement of urine calcium. Any secondary causes of bone loss should be identified and treated, as described earlier, to eliminate and treatable causes of bone loss and to recognize any factors that may increase the patient’s risk of fracture. Bone density should be determined at baseline by DEXA to establish risk of osteoporosis on the basis of WHO criteria.
Despite the severity of the bone loss in some patients with steroid use, there are few prospective, randomized, controlled investigations of therapeutic interventions in these patients. A prophylactic graduated exercise program, as clinically feasible, may prevent the bone loss that results from immobilization and inactivity. In patients who are taking corticosteroids, calcium, 100 mg/day, inhibits bone resorption and decreases bone loss. Thus, patients should be advised to maintain adequate calcium intake, as discussed earlier for osteoporosis. Buckley and coworkers showed that calcium , 1 g/day, with vitamin D3, 500 IU/day, over 2 years in patients with RA taking more than 5 mg of prednisone daily, prevented bone loss at the spine and hip at rates of 2% and 0.9%, respectively. Adachi and colleagues randomly assigned 62 steroid-using patients, each for 36 months. Bone density twice as fast in the steroid-treated patients; at 18 months, after the steroid dose was reduced to less than 7.5 mg/day, an increase in BMD was noted. Overall, the steroid users who took calcium and vitamin D had a 4.2% reduction in BMD, in comparison with a 9% decrease in the placebo recipients.
It was found that 1,25(OH)2 vitamin D was ineffective in prevention of corticosteroid-induced osteoporosis. However, as primary prevention, calcium and 1,25(OH)2 vitamin D, with or without calcitonin, reduced vertebral bone loss in corticosteroid treated subjects. Calcitonin therapy had sustained effect during the second year when the other treatments were stopped. Hahn and coworkers showed in rheumatic patients taking corticosteroids that Vitamin D (50,000 U two to three times weekly) and 25-hydroxy-vitamin D (approximately 40 µg/day), each with 500 mg of elemental calcium daily, increased intestinal calcium absorption, suppressed PTH release, and had beneficial effects on bone density (approximately 8% and approximately 16% increments, respectively), although these were not long-term studies. Because of the negative calcium balance resulting from corticosteroid therapy, vitamin D supplementation raises the patient’s 25-hydroxyvitamin D level to the upper range of normal and appears to offset the negative calcium balance. Careful monitoring of the serum and urinary calcium levels in necessary in order to minimize the risk of vitamin D intoxication.
In a corticosteroid-treated patient who has an elevated urinary calcium lever (>4mg/kg/daily), possibly as a consequence of corticosteroid therapy or who develops hypercalciuria coincidentally with vitamin D treatment, hydrochlorothiazide therapy (25 to 50 mg two time daily) with a sodium-restricted diet is effective in reducing urinary calcium excretion. RA has been associated with a higher incidence of renal calculi and with hypercalciuria. In the absence of corticosteroid therapy, hydrochlorothiazide is associated with an 8% increase in BMD at the spine and 3% increase at the hip per year, higher bone density at multiple sites, and a reduction in the risk of hip fractures.
Hypogonadism should be treated regardless of whether the patient is postmenopausal, as discussed earlier. In a randomized crossover trial Reid and associates studied men treated with long-term glucocorticoids for asthma and randomly assigned them to receive 250 mg of intramuscular testosterone monthly or placebo monthly for 1 year, and therapy was crossed over for the second year. All men had low free testosterone levels (330 to 380 pmol/L) before treatment, before treatment, and testosterone therapy increased level to the hish normal range (1230 pmal/L0. In the treatment group, bone density increased by 5% at the spine but not at the hip, and alkaline phosphate and urinary hydroxyproline level decreased significantly. There were not adverse effects on lipid profiles or prostate cancer risk, and an increase in lean body mass and decrease in total body fat were noted. In men with testosterone deficiency resulting from corticosteroid therapy, treatment with parenteral testosterone (250 mg intramuscularly every 3 weeks) or a transdermal testosterone preparation (2.5 to 5 mg/day) may have beneficial effects on bone density in men with low pretreatment testosterone levels. Dosage is determined by the free testosterone levels should be monitored closely.
In a retrospective, case-control stud, treatment with estrogen, 0.625 mg/day, and progesterone, 5mg on days 15 to 25, prevented bone loss in corticosteroid-treated postmenopausal women receiving 5 to 15 mg of prednisone daily, resulting in a small but significant increase in spine BMD at 1 year. In patients with RA no treated with corticosteroids, a prospective, placebo-controlled study showed that estrogen replacement increased bone density in both the spine and the proximal femur. In a randomized controlled study, Hall and coworkers treated patients with RA with transdermal estradiol, 50 µg of estradiol should be used unless there is a contraindication. Further prospective, randomized, controlled studies of the effects or hormone replacement therapy on corticosteroid-induced bone loss are warranted.
The presence of enhanced bone resorption in corticosteroid treated subjects has led investigators to examine the effects of calcitonin, an osteoclast inhibitor, on BMD in a variety of patients with rheumatic diseases. Adachi and colleagues showed that patients with polymyalgia rheumatica who were treated with prednisone for one year had 3.7% less bone loss at the spine when treated with intranasal calcitonin, as opposed to placebo. A study of asthmatic patients with glucocorticoid induced osteoporosis that received steroids, calcium, and either intranasal calcitonin or placebo showed a 10.6% difference in spinal BMD at 2 years; BMD was higher in the calcitonin-treated group, but there was no significant protection against fracture. Ringe and Welzel showed that parenteral calcitonin (100 units every other day) produced a small increase in bone density in the forearms of patients with rheumatic diseases, whereas bone density declined in the control group. A significant reduction in pain score was also noted. Kotaniemi and associates showed that in patients with active RA taking low-dose steroids, treatment with intranasal calcitonin, 100 IU/day, versus placebo and calcium, 500 mg/day, for 1 year, resulted in an increase in femoral neck BMD but no significant change at the spine. Several studies, including preliminary data from a large multicenter placebo-controlled trial, have shown that calcitonin maintains bone mass or produces a small increment in bone in patients with RA not treated with corticosteroids, although a 1.8% bone loss was noted in the control group. Healey and co-workers showed that patients treated with calcitonin injections maintained but had no increase in spinal BMD.
Unlike the antiresorptive drugs discussed earlier, fluoride stimulates bone formation. In a primary preventive study of patients without previous osteoporosis, fluoride produced an insignificant 2% increase in BMD at the spine, in comparison with a 3% decrease in the placebo recipients. Monofluorophosphate plus calcium produced a 9.3% increase in spine BMD in patients treated with prednisone for 6 years. Rickers and associates in a prospective randomized 24-week trial were unable to demonstrate an effect of calcium, fluoride, and vitamin D in preventing corticosteroid induced bone loss at a trabecular and cortical site in the forearm. Meunier and colleagues, however, in a 2-year study, observed a 63% increment in trabecular bone on histomorphometric analysis of iliac crest biopsy specimens from corticosteroid-treated patients, which is consistent with an anabolic effect of fluoride on trabecular bone in this group of patients. Increases I BMD seen with fluoride therapy have not led to a decrease in the risk of fracture in patients with osteoporosis, but no fracture data are yet available for steroid-treated patients. Longer-term, randomized, controlled studies demonstrating a beneficial effect of fluoride on the reduction of fractures would be necessary to establish a role for this therapy in the treatment of corticosteroid-induced bone loss.
Lane and coworkers studied the role of PTH in the treatment of glucocorticoid-induced bone loss in postmenopausal women. All women were treated with 5 to 20 mg of prednisone daily and were receiving estrogen replacement therapy. Patients were randomly assigned to receive either PTH, 400 IU/day, or placebo, with calcium and vitamin D; after one year of therapy, BMD increased by 9% at the lumbar spine. Markers of bone formation, osteocalcin and bone-specific alkaline phosphates, increased within 1 month and bone resorption markers increased later; fracture data are not yet available.
Increased osteoclastic activity is one of the mechanisms for increased bone resorption in RA. The use of the biophosphonates as antiresorptive therapy is proving to be beneficial in the treatment of corticosteroid-induced bone loss. In patients undergoing long-term corticosteroid therapy, a prospective placebo-controlled study of oral pamidronate (APD, or 3-amino-1-hydroxypropylidene-1, 1-biophosphonate) and calcium produced an approximately 20% increment in lumbar spine bone density over 1 year, with subsequent stable bone densities. However, the FDA for use in the United States does not approve oral pamidronate. Cortet and associates showed that in patients taking more than 7.5 mg of prednisone daily, etidronate, 400 mg/day versus, placebo, cycled every 76 days for 1 year with calcium, 500 mg/day, resulted in 0.3% increase in spinal BMD in etidronate recipients and a 2.79% decrease in placebo recipients. This overall 3% difference between groups is significant, but no changes were seen at the hip. Similarly, Adachi and colleagues showed an intermittent cyclical therapy with etidronate significantly decreased bone loss in the lumbar spine by 3.23% and in femoral trochanter by 4.14%. There was a trend toward fewer vertebral fractures in the etidronate-treated group. Side effects were mil, transient, and mostly gastrointestinal. A 1-year follow-up evaluation of these patients, after discontinuatiaton of the study, showed no accelerated bone loss in the etidronate-treated group. A pooled data analysis from Raux and coworkers showed that intermittent etidronate is effective at preventing corticosteroid-induced bone loss in subgroups defined by sex, menopausal status, and disease state (RA vs. polymyalgia rheumatica).
Intravenous pamidronate was studied as a primary preventive therapy in patients commencing long-term prednisone treatment (, 10 mg/dat). Treatment involved 90 mg of pamidronate recipients, whereas the control group had 5.3% and 5.3% reductions, respectively. A significant benefit is found when bisphosphonates are used at the outset of steroid therapy.
Saag and associates pooled data from two randomized, double blind trials, studying the effects of alendronate, 5 and 10 mg/day, and placebo on BMD in patients receiving more than 7.5 mg of prednisone per day for rheumatologic (54%) and other diseases. All patients received calcium, 800 to 1000 mg/day, and vitamin D, 250 to 500 IU/day. During the study, the median prednisone dosages decreased to 8.8 mg/day, 8.7 mg/day, and 9 mg/day, respectively, in each of the treatment groups. Over 48 weeks, the spinal BMD increased 2.1% and 2.9%, respectively, with a 0.4% decrease I the control group (significant). The femoral neck bone density increased by 1.2% and 1.0% in the alendronte groups, respectively, but decreased by 1.2% in the control group (significant). There was no significant reduction in the incidence of vertebral or nonvertebral fracture in either group. There was slight increase in the nonserious upper gastrointestinal symptoms in patients treated with 10mg of alendronate, but there were no other significant adverse effects. A 24-month outcome analysis of these patients, after a second year of therapy, revealed a 0.7% vertebral fracture rate in alendronate-treated patients, in contrast to 6.8% in control groups.
Risedronate a biophosphonate approved by the FDA for the treatment of Pagets’s disease of bone has been studied in the treatment of steroid-induced osteoporosis. Cohen and colleagues in a double blind, placebo-controlled trial of patients with primarily rheumatologic diseases who were starting long-term corticosteroid therapy, randomly assigned these patients to receive 500 mg of calcium for 1 year with risedronate, 2.5 mg; risedronate, 5mg; or placebo. At 1 year, treatment, 5 mg/day, decreased bone loss at the spine by 3.8% and at the femoral neck by 4.1%. Reid and associates studied premenopausal women, postmenopausal women, and men with rheumatologic diseases; the patients were divided into two groups: those commencing steroid treatment, 7.5 mg for less than 3 months (to study prevention) and those taking long-term steroids, 7.5 mg for more than 6 months (to study treatment). All patients received 500 to 1000 mg of calcium plus 400IU of vitamin D per day, with 2.4 mg or 5 mg of risedronate or placebo daily. The prevention study showed that risedronate, 5 mg/day, resulted in 0.5%, 0.8% and 1.3% increases in BMD at the lumbar spine, femoral neck, and trochanter, respectively, but no increase in BMD with 2.5 mg of risedronate and a continued loss of up to 3% I the increased BMD. The vertebral fracture incidence was significantly lower in patients treated with risedronate, 5 mg, than in controls. Risedronate was well tolerated, with no significant increase in gastrointestinal side effects. The American College of Rheumatologists proposed the use of bisphosphonates in patients with corticosteroid-induced osteoporosis for whom hormone replacement therapy is contraindicated or refused or as an additional therapy if the BMD is low or continues of decrease despite hormone replacement therapy.
Studies show that the prednisone derivative deflazacort appears to have fewer effects on bone metabolism then does prednisone. At comparable anti-inflammatory dosages, deflazacort decreased BMD less than did prednisone (3% loss vs. 9.1% loss) at the spine, but no protection against the development or reduce the severity of corticosteroid-induced osteoporosis.
AUTHORS’ APPROACH TO MANAGEMENT
In corticosteroid treated patients, an initial approach is to select to lowest corticosteroid dosage possible to treat the underlying disease process. Alternatives to corticosteroid therapy for the rheumatic process may be considered in patients whenever possible, particularly in patients with accelerated bone loss. Not all patients treated with corticosteroids develop osteoporosis, however; the identify those at risk, we obtain a bone density determination a baseline and repeat it at 1 year in patients starting long-term (>3 months) corticosteroid therapy (>5 to 7.5 mg/day). This allows us to correct any secondary causes loss before steroid-induced changes occur and to institute therapy to protect the skeleton from steroid-induced osteoporosis when necessary. Bone densitometry are monitored to assess the skeletal response to a treatment intervention so that modifications in therapy may be instituted appropriately.
At baseline in a patient with osteopenia or osteoporosis, other secondary causes of bone loss are vigorously sought and treated. All patients are advised to modify any lifestyle factors that increase the risk osteoporosis; for example, smoking and excessive alcohol consumption. A physical activity program, including weight bearing exercised for 30 to 60 minutes per day, is recommended. Patients should be advised with regard to fall prevention strategies. To minimize the corticosteroid-induced negative calcium balance, we recommend adequate calcium intake (1000 mg for premenopausal women). Vitamin D, 400 to 800 IU/day, or supraphysiologic dosages of vitamin D (e.g., 50,000 IU of vitamin D weekly or bimonthly) may be necessary to maintain the 25-hydorixyvitamin D level in the uppe4r normal range exceeding 25 ng/mL. Careful monitoring of the serum and urinary calcium concentrations is essential for preventing the development of hypercalcemia, hypercalciuria (24-hour urine calcium level, >250mg), and nephrolithiasis. Hydrochlorothiazide therapy (25mg twice daily) may reduce the hypercalciuria associated with corticosteroid therapy concurrent calcium or vitamin D therapy, is necessary. Treatment of hypogonadism is essential; if there are no contraindications, as discussed earlier, we use gonadal steroid replacement in both the prevention and treatment of corticosteroid-induced bone loss in premenopausal women, postmenopausal women and hypogonadal men.
Corticosteroid-treated patients may benefit from additional therapy to prevent or treat osteoporosis in patients with evidence of an increased risk of fracture, reduced bone mass, or previous fractures. Additional therapies are recommended foe patients with a T score of less than –1. Patients with a normal BMD should have a follow-up BMD measurement at 6-12 months; is there has been more than a 5% loss, and if no secondary causes of bone loss that can be corrected are identified, additional therapy should be instituted. In patients with a previous fracture, pain relief may be an issue; calcitonin has been show to have an analgesic effect in the treatment of vertebral fractures. Premenopausal women should not be treated with bisphosphonates, although these agents appear to have the most potent effects I reducing bone loss both as a preventive and therapeutic intervention. They are not used in younger patients because of a theoretical concern regarding the long half-life of these drugs in the bone matrix. Intranasal calcitonin, 200 IU/day, alternate nostrils on alternate days to reduce nasal irritation and rhinorrhea, is well tolerated. Alendronate, 5mg/day, may be used to prevent further bone loss in patients with osteopenia. The FDA as a therapy for gulcocorticoid-induced osteoporosis has approved Alendronate, 10 mg/day. Alendronate should be taken with care, as described earlier, to optimize absorption and to minimize side effects. Risedronate, 5mg/day, has been approved by the FDA for the prevention and treatment of osteoporosis and glucocorticoid-induced osteoporosis. Intravenous pamidronate may be considered. When a patients treated with corticosteroids continues to lose bone or develops fractures while receiving a given intervention to protect bone mass, we reevaluate for concurrent secondary causes of bone loss and consider additional or alternative treatment options.
Glucocorticoids are essential in the treatment of many medical conditions, including pulmonary and several rheumatologic diseases. However, the disabilities resulting from glucocorticoid-induced osteoporosis and fractures are extensive. Information regarding the severity and prevalence of this disease is emerging from ongoing research, and physician awareness needs to be encouraged. Strategies for the management and prevention of steroid-induced bone loss are now available, as are the therapeutic interventions. Early recognition of the risk off bone loss and prompt intervention are essential for optimizing care for patients who requite glucocorticoid treatment.