454 Secondary Causes of Osteoporosis Mayo Clin Proc, May 2002, Vol 77 Table 1. Secondary Causes of Osteoporosis Endocrine disorders Acromegaly Adrenal

Transcription

1 Mayo Clin Proc, May 2002, Vol 77 Secondary Causes of Osteoporosis 453 Review Secondary Causes of Osteoporosis LORRAINE A. FITZPATRICK, MD Secondary causes of bone loss are not often considered in patients who are diagnosed as having osteoporosis. In some studies, 20% to 30% of postmenopausal women and more than 50% of men with osteoporosis have a secondary cause. There are numerous causes of secondary bone loss, including adverse effects of drug therapy, endocrine disorders, eating disorders, immobilization, marrow-related disorders, disorders of the gastrointestinal or biliary tract, renal disease, and cancer. Patients who have undergone organ transplantation are also at increased risk for osteoporosis. In many cases, the adverse effects of osteoporosis are reversible with appropriate intervention. Because of the many treatment options that are now available for patients with osteoporosis and the tremendous advances that have been made in understanding the pathogenesis and diagnosis of the condition, it is important that medical disorders are recognized and appropriate interventions are undertaken. This article provides the framework for understanding causes of bone loss and approaches to their management. Mayo Clin Proc. 2002;77: BMD = bone mineral density; CI = confidence interval; IGF = insulin-like growth factor; IL-1 = interleukin 1; PTH = parathyroid hormone; PTHrP = parathyroid hormone related peptide; RR = relative risk; TNF-α = tumor necrosis factor α; WHO = World Health Organization The past few years have been marked by tremendous advances in the understanding of the pathogenesis, diagnosis, and treatment of osteoporosis. Use of smaller devices and faster measurements of bone mass combined with the numerous randomized, placebo-controlled clinical trials have provided additional information to support diagnostic and therapeutic interventions for the clinician. Many new treatment options are available for the patient, and some treatment options have been explored in varying combinations. Primary osteoporosis is bone loss that occurs during the normal human aging process. Secondary osteoporosis is defined as bone loss that results from specific, well-defined clinical disorders. Many times reversible, secondary causes of bone loss are not considered in a patient with low bone mineral density (BMD). Secondary osteoporosis may be due to a large and diverse group of medical disorders, which includes endocrine disorders, adverse effects of medications, immobilization, disorders of the gastrointestinal or biliary tract, renal disease, and cancer (Table 1). It is important to determine the cause of the bone loss before finalizing decisions regarding treatment. ESTIMATES OF THE INCIDENCE OF SECONDARY OSTEOPOROSIS One of the challenges encountered in the discussion of secondary osteoporosis is understanding the problems of From the Division of Endocrinology, Diabetes, Metabolism, Nutrition and Internal Medicine, Mayo Clinic, Rochester, Minn. Address reprint requests and correspondence to Lorraine A. Fitzpatrick, MD, Endocrine Research Unit, Mayo Clinic, 200 First St SW, Rochester, MN ( fitzpatrick.lorraine@mayo.edu). the disorder in the general population. Cost concerns have limited use of thorough work-ups to rule out all possible secondary causes, or studies may reflect experiences from subspecialty clinics or tertiary medical care centers where inherent bias may be present. A small proportion of women with low trauma fractures have osteomalacia, and in men with femoral fractures, osteomalacia is present in 4% to 47%, with most studies 1 reporting a rate of close to 20%. It is not known whether populations with other fractures, such as vertebral fractures, or those without fractures have similar proportions of osteoporosis and osteomalacia. Since the treatment of osteomalacia is different from that of osteoporosis, this is an important distinction to make for optimal patient treatment. In a retrospective study 2 of 237 patients who attended a specialty osteoporosis practice, secondary causes for reduced BMD were evaluated in 196 postmenopausal women and 41 premenopausal women. Sixteen percent of these patients had 25-hydroxyvitamin D levels of less than 15 ng/ml, the lowest acceptable level without a concomitant rise in immunoreactive parathyroid hormone (PTH) levels. By using the World Health Organization (WHO) definition of osteopenia based on T score ( 1.0 to 2.5), 11% of osteopenic patients had 25-hydroxyvitamin D levels of less than 15 ng/ml. This finding suggests that if BMD is used as a criterion to define which patients undergo additional evaluation, then a significant portion of osteopenic (not osteoporotic) patients with vitamin D deficiency, one of the secondary causes for low BMD, would be missed. In a separate study 3 in an outpatient rheumatology department, causes of osteoporosis in 81 osteoporotic men Mayo Clin Proc. 2002;77: Mayo Foundation for Medical Education and Research

2 454 Secondary Causes of Osteoporosis Mayo Clin Proc, May 2002, Vol 77 Table 1. Secondary Causes of Osteoporosis Endocrine disorders Acromegaly Adrenal atrophy in Addison disease Cushing syndrome Eating disorders Endometriosis Gonadal insufficiency (primary or secondary) Hyperparathyroidism Hyperprolactinemia Hyperthyroidism Hypogonadism Type 1 diabetes mellitus Nutritional disorders Tumor secretion of parathyroid hormone related peptide Gastrointestinal disease Alcohol-related liver diseases Celiac disease Chronic active hepatitis Chronic cholestatic diseases Gastrectomy Inflammatory bowel disease Jejunoileal bypass Malabsorption syndromes Pancreatic insufficiency Parenteral nutrition Primary biliary cirrhosis Severe liver disease Marrow-related disorders Amyloidosis Hemochromatosis Hemophilia Leukemia Lymphoma Mastocytosis Multiple myeloma Pernicious anemia Sarcoidosis Sickle cell anemia Thalassemia Organ transplantation Bone marrow Heart Kidney Liver Lung Miscellaneous causes Ankylosing spondylitis Chronic obstructive pulmonary disease Congenital porphyria Epidermolysis bullosa Hemophilia Idiopathic hypercalciuria Idiopathic scoliosis Multiple sclerosis Rheumatoid arthritis Genetic disorders Hypophosphatasia Osteogenesis imperfecta were evaluated, and 63 men (78%) had secondary osteoporosis. However, the 22% of patients who were diagnosed as having primary osteoporosis included 8 of the 18 patients with hypercalciuria, the reason for which was not clear. In men with vertebral crush fractures, some investigators 4 have suggested that 55% of men have a secondary cause of osteoporosis and 20% of these cases are due to hypogonadism. In a series of 214 women with vertebral crush fractures, % were found to have an underlying cause of osteoporosis or early menopause (36.4%) before the age of 45 years. Other estimates of osteoporosis in women suggested that approximately 20% of women who appear to have postmenopausal osteoporosis have an identifiable secondary cause, whereas the incidence of men with a secondary cause has been estimated to be as high as 64%. 6 SECONDARY OSTEOPOROSIS ASSOCIATED WITH DRUG THERAPY Glucocorticoids Decalcification of the skeleton was recognized as a clinical feature of Cushing disease as early as Glucocorticoid excess results in diffuse bone loss and may affect trabecular bone more than cortical bone. Bone loss is due to suppression of osteoblast function, inhibition of intestinal calcium absorption leading to secondary hyperparathyroidism, and increased osteoclast-mediated bone resorption. Bone loss is also promoted by direct stimulation of renal excretion of calcium by glucocorticoids. Hypogonadism may occur with the suppressive effects of glucocorticoids on the hypothalamic-pituitary axis. Bone density is reduced in 40% to 60% of patients with an endogenous glucocorticoid excess, and pathologic fractures have been observed in 16% to 67%. Rib and vertebral fractures are the most common, but the risk of hip fractures is doubled in glucocorticoid-treated patients. 7 Short-term studies have indicated that glucocorticoid-induced bone loss appears greater in the first 6 to 12 months of therapy, and some studies 8,9 have documented a 20% to 30% loss of trabecular bone within the first year of glucocorticoid use. The minimum dose of glucocorticoids associated with rapid bone loss is not established, but some studies 7,10 indicate that as little as 2.5 mg/d of prednisone produces considerable bone loss. Recently, inhaled glucocorticoid therapy was associated with a dose-related decrease in BMD at the total hip and trochanter ( g/cm 2 per puff per year of treatment). 11 This finding, along with a retrospective study 7 that indicated 2.5 mg of prednisone is associated with bone loss, suggests a lower threshold at which glucocorticoids cause skeletal harm. Fracture risk increases with dose and duration of glucocorticoid use. Glucocorticoid-induced osteoporosis is more severe in pa-

3 Mayo Clin Proc, May 2002, Vol 77 Secondary Causes of Osteoporosis 455 tients younger than 15 years, those older than 50 years, postmenopausal women, and patients with low body weight. 12 The effects of glucocorticoids on bone and mineral metabolism lead to rapid acceleration of bone loss. Although physiologic concentrations of glucocorticoids enhance the function of osteoblasts, prolonged exposure to superphysiologic doses inhibits collagen synthesis and differentiation of osteoblasts, reducing bone formation. In the osteoclast, physiologic concentrations of glucocorticoids enhance late stages of differentiation and function. In the presence of high doses of glucocorticoids or prolonged exposure, apoptosis of new osteoclasts occurs. The effect of glucocorticoids on bone resorption may also be mediated in part by secondary hyperparathyroidism. The long-term increase in PTH levels enhances osteoclast-mediated bone resorption, resulting in bone loss. Other effects of glucocorticoids include alterations in the production of prostaglandins, cytokines, and growth factors. Glucocorticoids inhibit the production of prostaglandins, such as prostaglandin E 2, which normally stimulate collagen and noncollagenous protein synthesis. 13 Glucocorticoids decrease cell replication, and collagen synthesis is partially reversed by prostaglandin E 2, so this inhibition results in decreased bone formation. 14 Pharmacologic concentrations of glucocorticoids inhibit the synthesis of insulin-like growth factor (IGF) 1. 13,15 Synthesized by bone cells, IGF-1 stimulates bone cell replication and collagen synthesis. Glucocorticoids can also affect IGF-binding proteins, which inhibit or enhance IGF activity. The composite effect of glucocorticoids to decrease IGF-binding protein 5 (which has an anabolic effect of the IGF system) and to decrease IGFbinding protein 3 and IGF-binding protein 4 (which inhibit anabolic effects) may have an overall effect to reduce bone formation. 16 In glucocorticoid-treated patients, a marked increase in osteoblast (30%) and osteocyte (5%) apoptosis was noted. 17 In ex vivo marrow cultures from mice, glucocorticoids inhibited proliferation and/or differentiation of the stromal cell osteoblast precursors at an early stage, reducing the number of mature, matrix-forming osteoblasts. 17 Serum and urine biochemical indices in patients with glucocorticoid-induced osteopenia are generally normal. Urinary markers of bone resorption may be elevated. Serum immunoreactive PTH levels may be normal or mildly elevated (secondary hyperparathyroidism). Serum alkaline phosphatase (bone fraction) activity and osteocalcin levels decline steadily after the initiation of glucocorticoid therapy, reflecting inhibition of osteoblast activity. Urinary calcium excretion may be increased during the first several months to years of steroid therapy because of the direct calciuric effect of glucocorticoids on the kidney. (For a comprehensive review of this subject, see the article by Manelli and Giustina. 18 ) Aseptic or avascular necrosis (osteonecrosis) is a serious complication of glucocorticoid therapy and occurs in 4% to 25% of patients. The most frequently affected areas are the head of the humerus and distal femur. Several theories are proposed for the cause of osteonecrosis, which include ischemia caused by microscopic fat emboli, mechanical problems due to ischemic collapse of the epiphyses due to osteoporosis and fatigue fractures, or increased interosseous pressure due to the fat accumulation as part of Cushing syndrome, leading to mechanical impingement and decreased blood flow. The most recent hypothesis suggests that glucocorticoids enhance osteoblast and osteocyte apoptosis. In the study by Weinstein et al, 19 evaluation of the femoral head of glucocorticoid-treated patients who underwent prosthetic hip replacement revealed apoptotic osteocytes and apoptotic cells lining the cancellous bone juxtaposed to the subchondral fracture crescent. Management of Glucocorticoid-Induced Osteoporosis The first principle in the treatment of patients with glucocorticoid-induced osteoporosis is use of the lowest effective dose of glucocorticoid with the shortest half-life. Awareness of potential problems can prevent and reverse the bone loss to some degree. Anyone taking glucocorticoids for more than 2 months should be considered at risk. General health measures that are applicable to patients with osteoporosis should be encouraged, such as weight-bearing exercise and good nutritional status. To prevent secondary hyperparathyroidism, a calcium intake of 1500 mg/d is usually recommended. Serum 25-hydroxyvitamin D levels should be maintained at the upper limits of normal, and even small degrees of vitamin D insufficiency should be treated and monitored. The American College of Rheumatology 20 published the guideline of 800 IU/d of cholecalciferol in patients receiving 5 mg/d or more of prednisone. The secondary hyperparathyroidism due to hypercalciuria can be managed with a thiazide diuretic, and often small doses ( mg/d) can significantly reduce urinary calcium loss. 21 Gonadal hormones should be assessed and replaced. Estrogen and/or progesterone replacement therapy in postmenopausal women or women with irregular menses should be initiated. Men with low testosterone levels should have adequate replacement of testosterone. If the patient is unable to take gonadal hormones and is osteopenic, bisphosphonate therapy should be initiated. Etidronate, alendronate, pamidronate, and risedronate have all been shown to prevent bone loss in patients taking glucocorticoids However, alendronate and risedronate

4 456 Secondary Causes of Osteoporosis Mayo Clin Proc, May 2002, Vol 77 Table 2. Drugs Associated With Bone Loss Aluminum Anticoagulants Anticonvulsants Cigarette smoking Cytotoxic drugs Excessive alcohol Excessive vitamin A Glucocorticoids and adrenocorticotropin Gonadotropin-releasing hormone agonists Heparin Lithium Tamoxifen (in the premenopausal patient) Beta carotene? Bile-acid binding resins have been approved by the Food and Drug Administration for treatment of glucocorticoid-induced osteoporosis and are the bisphosphonates commonly used in this setting. Patients should be monitored frequently. Bone density should be measured every 6 months for the first 2 years of therapy. If bone loss continues, then aggressive treatment with combination therapies is warranted. Anticonvulsant Medications Bone disease associated with anticonvulsant therapy is a form of osteomalacia. In this condition, high-turnover osteoporosis is often present. In the florid form of osteoporosis, bone changes, such as osteopenia and fractures, are associated with hypocalcemia, hypophosphatemia, and muscle weakness. Rickets has been observed in children taking anticonvulsant medication. Early reports 27,28 suggest that a large number of patients with epilepsy receiving anticonvulsants develop signs of rickets or osteomalacia, particularly if they are institutionalized. In these reports, rates were as high as 20% to 65%, and patients were at particularly increased risk for fracture during seizures. In the outpatient setting, abnormalities on bone biopsy specimens, such as increased osteoid, are observed in 10% to 40% of patients receiving long-term anticonvulsant therapy. 29,30 In the outpatient setting, biochemical abnormalities, such as reduced serum and urine calcium levels, reduced serum 25-hydroxyvitamin D levels, and elevated serum PTH and alkaline phosphatase levels, are often noted. The mechanism by which anticonvulsants induce bone disease is thought to be drug metabolism by the liver. Phenobarbital, diphenylhydantoin, and carbamazepine, 3 of the most commonly used anticonvulsants, increase the metabolism and clearance of vitamin D. 31,32 Anticonvulsants such as sodium valproate have little or no impact on serum calcium and 25-hydroxyvitamin D levels because they do not induce hepatic drug metabolites and enzymes. 33 If the patient is well nourished and exposed to adequate amounts of sunlight, clinically significant bone disease is less likely to occur as a result of anticonvulsant therapy. In general, recommendations include higher intakes of cholecalciferol ( IU/d), with doses up to 4000 IU/d sometimes needed to achieve normal 25-hydroxyvitamin D levels. Miscellaneous Medications Associated With Osteoporosis Other medications have been associated with the development of osteoporosis (Table 2). Methotrexate has been implicated as a cause of bone loss, but in most studies, other drugs have been administered or the gonadal status of the patients has been altered, making definitive conclusions difficult. The administration of excessive exogenous thyroid hormone has been associated with osteopenia. Clinical relevance of osteoporosis associated with iatrogenic hyperthyroidism has been examined in terms of development of fractures, but the data remain controversial. Heparin has been implicated in the suppression of bone formation. Bile acid binding resins, such as cholestyramine and colestipol, have the potential to interfere with vitamin D absorption. Aluminum is a well-known inhibitor of bone mineralization and phosphate absorption. Aluminum-induced osteomalacia can be present in patients who are undergoing hemodialysis or taking total parenteral nutrition. Antacids are used to control serum phosphate levels in patients with renal failure, and aluminum contamination of various components can occur during total parenteral nutrition. In patients with aluminum-induced osteomalacia, normal or even high serum phosphate levels and low 1,25- dihydroxyvitamin D levels occur. 34 Patients with renal failure may have a lower-than-expected PTH level and become hypercalcemic at low doses of calcitriol. 34 Reduction of aluminum exposure of these patients has reduced the incidence of aluminum-induced osteomalacia. Deferoxamine is used to reduce the body load of aluminum and reduce osteomalacia. 35 ENDOCRINE DISORDERS ASSOCIATED WITH SECONDARY OSTEOPOROSIS Hyperthyroidism Both thyroid insufficiency and excess lead to alterations in bone mass. Thyroid hormone increases the creation of new bone remodeling units with an enhancement of remodeling activity. Thyroid hormones directly stimulate production of osteocalcin, alkaline phosphatase, and IGFs. In patients with thyrotoxicosis, increased serum levels of osteocalcin and alkaline phosphatase may be seen. Despite the increase in osteoblast activity, there are also thyroid hormone induced increases in bone resorption. The bone resorption is associated with increased levels of hydroxy-

5 Mayo Clin Proc, May 2002, Vol 77 Secondary Causes of Osteoporosis 457 proline and collagen cross-links in thyrotoxic patients. The overall increase in bone turnover in the presence of excessive levels of thyroid hormone is characterized by an increase in the number of osteoclasts, the number of resorption sites, and the ratio of resorptive to formative surfaces. In the thyrotoxic patient, the bone remodeling cycle is shortened because of a decrease in the length of the bone formation and, overall, there is failure to replace resorbed bone completely, leading to bone loss. 36 In patients with thyrotoxicosis, BMD is reduced. 37 Several studies 38 have indicated that individuals with a history of thyrotoxicosis have an increased risk of fracture and may sustain fracture at an earlier age compared with patients who have never had an increase in thyroid hormone levels. After effective treatment of the thyrotoxic patient, the decrease in bone density may be reversible. Normalization of the results of thyroid function tests results in increases in bone density compared with pretreatment values. 37 Concerns about the effects of administration of high doses of thyroid hormone to suppress thyrotropin secretion in patients with differentiated thyroid cancer or nontoxic goiter have led to several studies in bone metabolism. 39 It is thought that in patients who have risk factors for osteoporosis, this type of therapy may aggravate fracture risk. There have been controversial studies regarding whether thyrotropin-suppressive doses of thyroid hormone will decrease or have no effect on BMD in women. In 1 metaanalysis, 40 BMD was assessed in women receiving thyrotropin-suppressive doses of thyroxin. The study concluded that there was a 1% increase in annual bone loss in postmenopausal women. Only 1 large prospective study, the Study of Osteoporotic Fractures, 38 examined the relationship between thyroid disease and fractures. In this study, postmenopausal women with a history of hyperthyroidism had an 80% increase in the risk of subsequent hip fracture. Thyroid hormone use itself was associated with a 60% increase in risk. Unfortunately, this study did not include measurements of thyroid function. Because there are no published prospective studies of the relationship between thyroid function assessed by measurements of thyrotropin levels and subsequent fracture, debate continues about the appropriate levels that may result in an increased risk for an individual patient. One recently published study 41 evaluated the influence of vitamin D receptor polymorphisms on BMD in patients with hyperthyroidism in an attempt to define a genetically programmed high-risk group. The cumulative risk for low BMD in patients with hyperthyroidism and the BB genotype was 31.4 (95% confidence interval [CI], ). The authors suggest there may be a synergy for the development of low BMD in hyperthyroid patients with the BB vitamin D receptor phenotype. Primary Hyperparathyroidism Parathyroid hormone is responsible for maintaining calcium homeostasis through its action on target cells in the bone and kidney. Primary hyperparathyroidism is a common disorder, with an incidence of 1 in 500 to 1 in 1000, and is usually asymptomatic. 42 Classically, primary hyperparathyroidism is associated with specific skeletal disorders. These disorders include osteitis fibrosa cystica in which subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, a salt and pepper appearance of the skull, brown tumors, and bone cysts of the long bones occur. With screening of the patients for asymptomatic hypercalcemia, the incidence of bone disease of this type is rare. Osteopenia and osteoporosis are also recognized as bone diseases associated with excess PTH. The pathophysiology of primary hyperparathyroidism relates to the loss of normal feedback control of PTH by extracellular calcium. The parathyroid cell loses its normal sensitivity to calcium, and this is the major mechanism in parathyroid adenomas. In primary hyperparathyroidism due to hyperplasia, the set point for calcium is not changed for a given parathyroid cell, but an increased number of cells gives rise to hypercalcemia. The increase in circulating levels of PTH in primary hyperparathyroidism is associated with increased bone turnover. There is an increase in both osteoclast-mediated bone resorption and osteoblast activity. Overall, there is loss in both cortical and cancellous bone. In mild hyperparathyroidism, however, BMD may be increased in areas that are primarily cancellous, whereas bone is lost in the cortical areas. 43 This anabolic effect is the basis for intermittent administration of PTH as a therapeutic agent for the treatment of osteoporosis, because bone formation occurs at a more rapid rate than bone resorption. 44,45 In addition, PTH has clear-cut effects on osteoclast differentiation. The effects of PTH on osteoclast differentiation are mediated through the osteoblast or stromal cell component in the cell culture system. 46 Bone resorption is enhanced by sustained levels of PTH. Bone density has been measured at 3 sites to evaluate areas rich in cortical bone, cancellous bone, and a mixture of both. At the distal radius, an area rich in cortical bone, bone density was less than 80% of age- and sex-matched control values in a cohort of patients with primary hyperparathyroidism. In contrast, at the lumbar spine, which reflects cancellous bone, BMD was relatively well preserved. The values for the hip region, which is made of mixed cancellous and cortical bone, were midway between the data obtained for the spine and the distal radius. 47 This finding is consistent with the observation that PTH mobilizes calcium from cortical sites before it has a negative impact on cancellous skeleton. Quantitative histomorpho-

6 458 Secondary Causes of Osteoporosis Mayo Clin Proc, May 2002, Vol 77 metric analysis of bone biopsy specimens is consistent with the loss of cortical bone and preservation of cancellous bone. 43 The static parameters of bone, such as osteoid surface, osteoid volume, and eroded surfaces, are elevated in women with primary hyperparathyroidism, consistent with an increased bone turnover. The dynamic parameters (mineralizing surface and bone formation rate) are also elevated. Cortical thinning is noted on biopsy specimens, and PTH levels correlate with cortical porosity. 48 After surgical cure of primary hyperparathyroidism, BMD increases in both the forearm and lumbar spine. In a longitudinal cohort of patients with primary hyperparathyroidism followed up for 10 years, 47 parathyroidectomy resulted in normalization of biochemical values and increased BMD. The increase in bone density was prompt and sustained, but a trend toward further increase after 1 year was significant only for femoral neck values. In a subset of patients who did not undergo surgery, there was no progression of bone disease if they were asymptomatic, but one quarter had some progression with bone loss. Several studies have assessed the risk of fracture in patients with primary hyperparathyroidism. In a population-based study 49 of 407 patients with primary hyperparathyroidism in Rochester, Minn, there was an increased incidence of vertebral, Colles, rib, and pelvic fractures. In this study, the fracture incidence at each site was compared with the number expected from sex- and age-specific fracture incidence rates for the general population. The community of patients in this cohort had mild hyperparathyroidism, with a mean (±SD) serum calcium level of 10.9±0.6 mg/dl. The increased risks of fracture were 3.2 (95% CI, ) for vertebral fracture, 2.2 (95% CI, ) for forearm fracture, 2.7 (95% CI, ) for rib fracture, and 2.1 (95% CI, ) for pelvic fracture. By multivariate analysis, age and female sex remained significant independent predictors of fracture risk. Unfortunately, this set of patients was not characterized regarding BMD. A recently published study 50 evaluated 674 consecutive patients with primary hyperparathyroidism at 3 Danish university hospitals. These individuals were matched for age and sex to a national patient register. There was an increased relative risk (RR) of fractures in the hyperparathyroidism cohort compared with controls (RR, 1.8; 95% CI, ) before surgery. After surgery, the RR was 1.0. The risks for fracture were increased for the vertebrae (RR, 3.5; 95% CI, ), the distal part of the lower leg and ankle (RR, 2.3; 95% CI, ), and the nondistal part of the forearm (RR, 4.0; 95% CI, ) before surgery, but these increases were not seen after surgery. The risk increased in patients 5 to 10 years before surgery. There may have been some selection bias in this study, but the increased rates of fracture are consistent with several other published studies. 49,51-53 Acromegaly Elevated concentration of growth hormone causes acceleration of bone turnover with an increase in osteoblast and osteoclast activity. In patients with acromegaly, the frequency of osteoporosis or fractures does not appear to be increased. However, in some studies, 54,55 bone mass has proved to be increased, and elevated 1,25 hydroxyvitamin D levels have been noted. When osteoporosis occurs in acromegaly, the bone in this setting is of unusual architecture and composition. There is usually a very low trabecular bone volume similar to postmenopausal osteoporotic patients, whereas cortical bone is less altered. 56 Growth hormone can increase tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) secretion by mononuclear cells, and these cytokines have been implicated in postmenopausal osteoporosis. In a study 57 of 11 patients with active acromegaly, BMD was significantly reduced at the lumbar spine but not at the femoral neck compared with that in sex-, weight-, and age-matched controls. However, circulating levels of IL-1 and TNF-α were the same in acromegalic patients and controls. In acromegaly, the pituitary disease or its treatment may cause hypogonadism, resulting in bone loss. Cushing Syndrome or Disease Hypercortisolism is a well-recognized risk factor for the development of osteoporosis (see Glucocorticoids section). This occurs in exogenous or iatrogenic hypercortisolism, and trabecular bone tends to be lost in preference to cortical bone. If excess cortisol is cured surgically, some of the bone loss is reversible. In a small study 58 of 2 patients, BMD improved as much as 20%. In a clinical trial, 59 alendronate, which is used for treatment of glucocorticoid-induced osteoporosis, was given to a group of 39 patients with Cushing disease who were treated with ketoconazole. In this study, BMD was significantly increased at the lumbar spine and femoral neck after 1 year of treatment with the bisphosphonate. Type 1 Diabetes Mellitus Low BMD is associated with type 1 diabetes mellitus. No increase in the incidence of fracture in diabetic patients compared with a nondiabetic population has been noted, but the incidence of stress fractures in foot bones is higher in diabetic patients than in nondiabetic patients. Bone formation rates are low in patients with type 1 diabetes mellitus, and the reduction in bone turnover rates may cause the bone to be more fragile, resulting in the risk of fracture in a subset of patients. 60,61 Although these aberrations are fairly well documented, the mechanism of bone loss in diabetic patients remains controversial. In a study 62 of patients with type 1 and type 2

7 Mayo Clin Proc, May 2002, Vol 77 Secondary Causes of Osteoporosis 459 diabetes compared with control subjects, patients with type 1 diabetes had lower BMD at the spine and hip, reaching statistical significance in the female subgroup. Patients with type 1 diabetes had lower IGF-1 and IGF-binding protein 3 levels, and IGF-binding protein 1 and IGF-binding protein 4 correlated negatively with BMD of the hip. In the patients with type 2 diabetes in whom immunoreactive proinsulin was detected, proinsulin levels correlated with BMD of the hip. The investigators suggest that abnormalities in the IGF system and the lack of endogenous proinsulin contribute to the lower BMD levels in patients with type 1 diabetes. 62 Hyperprolactinemia Hyperprolactinemia occurs in physiologic conditions such as pregnancy and lactation and also occurs secondary to pituitary or hypothalamic diseases. High levels of prolactin inhibit gonadotrophic-releasing hormone, resulting in hypogonadotrophic hypogonadism. It has been estimated that as many as 25% to 30% of premenopausal women with amenorrhea may have hyperprolactinemia. 63,64 Hyperprolactinemia is associated with reduced bone mass. 65 Both men and women with a history of prolactinemia and hypogonadism for more than 10 years have lower BMD values than patients who were recently diagnosed as having these conditions. This finding suggests that the severity of bone loss in patients with hypoprolactinemia is related to the presence and duration of hypogonadism. One factor that may be responsible is a potent stimulator of bone resorption, PTH-related peptide (PTHrP). In patients with hyperprolactinemia, higher levels of PTHrP are noted compared with sex- and age-matched controls. 66 These levels are negatively correlated with BMD z scores in these patients. 67 Patients with higher PTHrP levels have significantly higher mean serum calcium, total alkaline phosphatase, and osteocalcin levels. Few studies have looked at biochemical markers of bone remodeling in patients with hyperprolactinemia. Total alkaline phosphatase levels have been reported to be normal. However, osteocalcin levels were low and returned to normal after therapy with dopamine agonists. 68,69 Urinary N-telopeptide levels are increased and also returned to normal values after treatment with dopamine agonists, suggesting that increased resorption is the major pathologic finding in hyperprolactinemia. MISCELLANEOUS CAUSES OF SECONDARY OSTEOPOROSIS Eating Disorders Anorexia nervosa and bulimia affect 5% to 10% of women. 70 Onset may be at any time from adolescence through the fourth decade of life. These eating disorders are resistant to treatment and chronic in nature, which results in significant morbidity and mortality. Anorexia nervosa has been associated with osteoporosis. There are several metabolic disorders associated with anorexia nervosa that may adversely affect the skeleton. These include estrogen deficiency, endogenous cortisol excess, reduced IGF-1 levels, protein-energy malnutrition, and secondary hyperparathyroidism due to low dietary calcium intake or vitamin D deficiency. It has been estimated that 50% of anorexic patients have bone density values of the lumbar spine that are more than 2 SDs below those of age-matched, healthy controls. 71 Diagnosis may be difficult because patients are resistant to seeking medical help and treatment. Total alkaline phosphatase activity may be elevated, but liver enzyme levels are also elevated, suggesting hepatic function may be altered. Osteocalcin, a marker of bone turnover, has been noted to be very low in women with anorexia nervosa and may be due to the excess endogenous cortisol levels. Markers of bone resorption, such as pyridinoline and N- telopeptide excretion, are usually increased and inversely correlated with BMD. The reduction in bone formation parameters and increase in levels of bone resorption markers suggest that bone remodeling is uncoupled. Serum vitamin D concentrations are highly variable and are affected by reduced dietary intake and diminished hepatic synthesis or binding capacity of vitamin D binding proteins in patients with estrogen deficiency. Elevated serum and urinary cortisol levels are common in women with anorexia nervosa. Hypercortisolism results from both increased production and decreased cortisol clearance as a result of the enhanced activity of the hypothalamic-pituitary-adrenal axis. 72 Elevated growth hormone and suppressed IGF-1 levels have been described in these patients and may be due to prolonged nutritional deprivation and be responsible for the enhanced bone loss. 73 Immobilization Immobilization causes a rapid and diffuse bone loss. The nature and mechanics of normal bone stress have been intensely studied. When healthy adults are placed on bed rest, hypercalciuria develops and persists for months. Whole body mineral loss of about 0.5% per month can occur, and remineralization begins once ambulation is resumed. Data from space flights have revealed the critical importance of gravitational stress. Despite frequent strenuous exercise, astronauts in weightless orbit experience impressive hypercalciuria and a negative calcium balance. 74 In healthy volunteers on bed rest, the total projected yearly loss in hip and spine BMD is more than 10% and calcaneal loss exceeds 50%. 75,76 In a recent study 77 in which healthy patients underwent 12 weeks of bed rest, BMD declined at the spine and hip by 2.9% and 3.8%, respectively. Bed rest resulted in signifi-

8 460 Secondary Causes of Osteoporosis Mayo Clin Proc, May 2002, Vol 77 cantly increased levels of urinary calcium and phosphorus and serum calcium. Bone histomorphometric studies revealed a suppression of osteoblast surfaces and increased bone resorption, manifesting an increase in eroded surfaces. Surprisingly, serum biochemical markers of bone formation did not change, but biochemical markers of bone resorption significantly increased during bed rest and declined toward normal during reambulation. 78,79 Patients with paresis, stroke, quadriplegia, paraplegia, fracture, or prolonged bed rest after surgery are all at high risk for the development of osteoporosis. Hypervitaminosis A Hypervitaminosis A results in weakness, emotional lability, musculoskeletal pain, headache, pseudotumor cerebri, and osteopenia. Serum alkaline phosphatase activity (both bone and hepatic isoenzymes) may be elevated. It was noted that a higher incidence of osteoporosisrelated fractures was found in northern Europe. It was proposed that these fractures may be related to the high dietary intake of vitamin A. Hip fracture rates, BMD, and estimation of retinol intake were assessed in a cross-sectional and nested case-control study 80 in Sweden. Multivariate analysis revealed a negative association between BMD and vitamin A intake. For each 1-mg/d increase in vitamin A intake, hip fracture risk increased 68% (95% CI, 18%-140%). In a prospective analysis 81 with 18 years of follow-up, a group of 72,337 postmenopausal nurses were evaluated for hip fractures and vitamin A intake. Women in the highest percentile of vitamin A intake had a significantly increased RR of nontraumatic hip fracture (RR, 1.48; 95% CI, ; P=.003). Marrow-Related Disorders Cancellous and endocortical bone surfaces are in close opposition to the bone marrow, and disorders of bone marrow can produce profound changes in bone. Plasma cell dyscrasia, such as multiple myeloma and macroglobulinemia, are associated with bone disorders caused by an increase in bone-resorbing cytokines such as IL-1, TNF-α, and lymphotoxin. 82,83 Other disorders, such as leukemia, lymphomas, hemochromatosis, and systemic mastocytosis, can result in osteoporosis Chronic anemias, such as sickle cell anemia and β-thalassemia, are associated with bone loss, and bone diseases are common features of Gaucher disease and Niemann-Pick disease. 89,90 METABOLIC BONE DISEASE ASSOCIATED WITH GASTROINTESTINAL, PANCREATIC, AND HEPATIC DISORDERS The skeleton depends on the adequate supply of calcium, phosphate, and vitamin D from the diet. Abnormalities of the hepatogastrointestinal tract may impair absorption of vitamins and minerals, resulting in bone disease. Intestinal calcium absorption occurs throughout the intestine, but the highest rates of absorption are in the duodenum. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D, controls the transcellular pathway of calcium absorption. At low calcium intakes, the transcellular pathway dominates and is highly efficient. If calcium intake increases, nonsaturable but less efficient pathways, such as the paracellular pathway, become important. Gastrointestinal disease leads to abnormalities in bone primarily due to the malabsorption of vitamin D and calcium, although the presence of the disease itself may lead to reduced intake or limited exposure to sunlight. Protein and other micronutrient deficiencies may contribute to bone loss in gastrointestinal tract disorders. Secondary hyperparathyroidism may be a consistent feature in these vitamin D deficient patients with accelerated loss of cortical bone. When secondary hyperparathyroidism occurs, it is characterized by increased bone turnover with an increased surface area and volume of unmineralized tissue. Osteoporosis, pseudofractures, and fractures have been noted in patients after gastrectomy. In a large study 91 of older women, gastrectomy correlated with an 8.2% decrease in bone density. In other studies, 92 bone pain or tenderness has been observed in 26% of patients who underwent gastrectomy compared with 4% of controls. Bone biopsy specimens show widened osteoid seams in 32% of patients who underwent gastrectomy compared with 0 of 9 controls. Smokers appear to be at higher risk of fracture than nonsmokers. 93 There appears to be a sex difference in that female patients are more predisposed to developing bone disease following gastrectomy. 94 Peptic ulcer disease followed by gastrectomy is not an uncommon problem, but bone disease may not develop until several years after the procedure. Thus, it may be an older patient who presents with manifestations of postgastrectomy bone disease. Laboratory assessment reveals reductions in serum calcium and phosphate levels (although they may be within the normal range) and an increase in alkaline phosphatase activity and osteocalcin levels. Urinary calcium excretion tends to be low. The PTH levels may be normal or slightly elevated. In most studies, 25-hydroxyvitamin D levels were reduced. 1,25-Dihydroxyvitamin D levels may be slightly elevated, and the profile suggests mild hyperparathyroidism secondary to early vitamin D and calcium deficiency. Pseudofractures and fractures of the hip are less common but may occur. A mixed picture of both osteoporosis and osteomalacia may be present. Treatment of the bone disease can be complex, and the osteomalacic component should be treated with vitamin D and calcium supplements. Bone biopsy speci-

9 Mayo Clin Proc, May 2002, Vol 77 Secondary Causes of Osteoporosis 461 mens can distinguish between the 2 diseases, but if no biopsy specimen is obtained, a clinical trial with vitamin D and calcium is warranted. Serum levels of 25-hydroxyvitamin D can be used for monitoring. Bone Disease and Celiac Disease Bone disease associated with celiac disease can present as osteoporosis, osteomalacia, or both. Untreated adults usually present with reduced bone mineral at the time of diagnosis, whereas children may present with growth retardation. 95,96 In celiac disease, the upper small intestine is usually more affected than the ileum. Patients may present with normal serum biochemical analysis results or with reduced serum and urine calcium levels and elevated alkaline phosphatase levels. With a gluten-free diet, biochemical abnormalities and bone density measurements may improve. 97,98 Patients may present with spinal or rib fractures, and pseudofractures are uncommon. Inflammatory Bowel Disease Bone disease can be associated with inflammatory bowel disease, such as Crohn disease and ulcerative colitis. The incidence of bone disease has been estimated at 3% to 77% of patients. In a study by Schulte et al, 99 the incidence of osteopenia was 32% in patients with ulcerative colitis and 36% in those with Crohn disease. This study also found a 7% and 15% incidence of osteoporosis in patients with ulcerative colitis and Crohn disease, respectively. Skeletal bone disease is most frequently associated with Crohn disease, especially if treated with ileal resection and glucocorticoids. Either osteoporosis or osteomalacia may be present. The patients may present with bone pain, weakness, or elevated alkaline phosphatase activity. In Crohn disease, the biochemical and clinical features of bone disease may be subtle. Biochemical measurements are generally normal, but calcium, phosphorus, and magnesium levels may be low. Serum 25-hydroxyvitamin D levels are reduced in 65% of patients, particularly those who have undergone ileal resection. 100,101 Osteopenia is common, but less than 10% of patients will have fractures or pseudofractures. A bone biopsy specimen is the only way to distinguish with certainty between osteomalacia and osteoporosis. In Crohn disease, there are multiple reasons for the development of bone disease, because malabsorption results in the reduction of vitamin D and calcium absorption. The resection of part of the intestine may also result in reduced vitamin D absorption. Vitamin D metabolites that are undergoing enterohepatic circulation cannot be reabsorbed if the ileum is diseased or resected. Steatorrhea may occur, decreasing both calcium and vitamin D absorption. Glucocorticoid therapy is frequently used for active disease and can also contribute to calcium malabsorption and bone loss. Treatment is usually in the form of cholecalciferol ( ,000 U/d), although calcifediol may be better absorbed than cholecalciferol in patients with steatorrhea. Dietary counseling and/or supplementation of calcium is warranted. Jejunoileal Bypass Jejunoileal bypass is used to treat massive obesity, and the subsequent development of bone disease is becoming better recognized. Reductions in serum calcium and magnesium levels with an increase in alkaline phosphatase level is observed in many patients within 3 months of operation and may persist. Osteomalacia or reduced trabecular bone volume apparent on bone biopsy specimens has been found in up to 60% of unselected individuals, although osteoporosis or osteopenia may not be found. In another study, 102 evidence for osteomalacia has been found on bone biopsy specimens of 73% of 41 subjects 1 to 5 years after ileal-pancreatic bypass procedure for obesity. Parathyroid hormone levels may be normal, and reduction in bone density is generally not found. Malabsorption of vitamin D, calcium, and magnesium has been demonstrated, and fatty infiltration of the liver may be present. Calcium supplementation to normalize urine calcium levels and cholecalciferol have been used successfully to treat bone disease following jejunoileal bypass. DISEASES OF THE PANCREAS Pancreatic Insufficiency Clinically significant bone disease in patients with pancreatic insufficiency due to cystic fibrosis or total pancreatectomy is not unusual. In children or young adults with cystic fibrosis, reduced bone density has been found and may be confounded by variables such as glucocorticoid use and hypogonadism. 103,104 Clinical features include diabetes mellitus and steatorrhea. Steatorrhea probably has the most impact on vitamin D and calcium malabsorption. In a patient with bone disease secondary to pancreatic insufficiency, other complicating features, such as alcohol abuse, cholestasis, cirrhosis, or intrinsic small bowel involvement, should be evaluated. Patients with low 25-hydroxyvitamin D levels should be treated with sufficient amounts to restore serum levels to normal. Either dietary or supplementary calcium is also an important adjuvant therapy. DISEASES OF THE LIVER Liver diseases may cause bone disease because of the inability of the liver to convert vitamin D to 25-hydroxyvitamin D. The role of vitamin D depends on hepatically produced vitamin D transport proteins, albumin, and vitamin D binding protein. The development of bone disease

10 462 Secondary Causes of Osteoporosis Mayo Clin Proc, May 2002, Vol 77 also depends on the transport of vitamin D metabolites to the target tissues, the degree to which enterohepatic circulation of vitamin D as metabolites contributes to the maintenance of bone, and the role of bile in promoting vitamin D and calcium absorption, all of which may be affected by liver diseases. Chronic Cholestatic Diseases Primary biliary cirrhosis is the best-studied chronic cholestatic disease. It occurs most frequently in middleaged women, an age at which postmenopausal osteoporosis is common and may be difficult to distinguish from the osteoporosis associated with liver disease. In primary biliary cirrhosis, both osteoporosis and osteomalacia can occur concurrently. Patients with primary biliary cirrhosis are often asymptomatic, although they may present with bone pain and have osteoporosis or osteomalacia apparent on bone biopsy specimens. Serum and urine calcium, serum phosphorus, and serum magnesium levels may be normal or slightly reduced. In this setting, PTH levels may be low, but reports of elevated PTH levels have also been found. 105 Alkaline phosphatase activity may be elevated due to liver isoenzymes. Serum 25-hydroxyvitamin D levels decrease as the disease progresses, but serum 25-hydroxyvitamin D is not a good predictor of bone disease. 106 Patients with primary biliary cirrhosis have increased fracture rates, but decreased BMD and pseudofractures are rare. Children with biliary atresia may present with florid rickets. Even if biliary atresia is surgically corrected, there is a high likelihood of developing rickets, which is readily treated with cholecalciferol. Chronic Active Hepatitis Patients with chronic active hepatitis have less metabolic bone disease than patients with other liver diseases, unless they have been treated with glucocorticoids. Fortyseven percent of patients with chronic active hepatitis due to glucocorticoid hormones have osteopenia, but the prevalence of bone disease in the absence of treatment has not been established. 107 Bone disease is usually asymptomatic. Patients with chronic active hepatitis tend to have 25- hydroxyvitamin D levels below normal and a reduction in vitamin D binding protein levels, suggesting that free 25- hydroxyvitamin D may be normal. Osteomalacia is uncommon. Scarcity of data makes it problematic to suggest a pathogenic mechanism for bone disease in chronic active hepatitis. Vitamin D deficiency secondary to malabsorption or impaired hepatic conversion of vitamin D to 25- hydroxyvitamin D may be implicated. Glucocorticoid therapy is likely to be the most important player in the pathogenesis of bone disease in these patients. Limiting the use of glucocorticoid therapy, providing adequate nutrition, and encouraging sunlight exposure are the first treatment modalities. The role of cholecalciferol and calcium supplementation must be individualized. Alcohol-Related Liver Disease Bone disease due to alcoholism is not restricted to patients who develop cirrhosis. Alcohol abuse is a major cause of liver disease, and cirrhosis contributes to the severity of bone disease. Spinal osteopenia may be observed in up to 50% of ambulatory patients with alcoholism, and fractures of the ribs or vertebrae occur in 30% of this population. 108,109 The clinical picture may be complicated by past partial gastrectomy in some patients. Osteoporosis is usually the predominant disease, although osteomalacia may occur. Sex differences occur in that chronic alcohol abuse has a detrimental effect on the male skeleton, whereas a neutral or beneficial effect with light-to-moderate alcohol consumption is seen on the female skeleton. 110 Idiopathic osteoporosis may be the clinical presentation of alcohol-related liver disease. Serum concentrations of calcium, phosphorus, and magnesium tend to be in the low normal range, but in binge drinkers, the serum levels of these minerals may be sufficiently reduced to cause neuromuscular disturbances and rhabdomyolysis requiring hospitalization. Poor nutrition contributes to the picture, with a reduction in serum albumin levels. Serum PTH levels may be elevated or high normal and may be due to short-term administration of alcohol or the low calcium and magnesium levels. 25-Hydroxyvitamin D levels are usually low, and 1,25-dihydroxyvitamin D levels have been reported as low, normal, or high. Cancellous bone is more affected than cortical bone when evaluating BMD. 111 Fractures are common and pseudofractures are rare. Although initially it was thought that these patients presented with osteomalacia, the fact that osteoporosis is predominant has led to the hypothesis that the prime offender is alcohol or one of its metabolites. Alcohol directly inhibits bone cell activity, resulting in reduced bone formation and bone resorption. Cessation of alcohol consumption can reverse or at least stop progression of disease. If 25-hydroxyvitamin D levels are low, cholecalciferol therapy should be considered. Malabsorption is usually fairly mild, and ensuring adequate nutrition is appropriate. It is unclear how reversible the osteoporosis is in the disorder. TRANSPLANTATION OSTEOPOROSIS Organ transplantation has become an effective therapy for end-stage renal, hepatic, cardiac, and pulmonary disease. 112 One-year patient survival is excellent, averaging 98% for living donor kidney, 87% for liver, and 85% for cardiac transplant recipients. 113 Many patients now live for more than 10 years. Unfortunately, many transplant patients