Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, which leads to increased bone fragility and a consequent increase in fracture risk (1). In addition to the current definition of osteoporosis according to the World Health Organization (WHO) - a T-score of ≤-2.5 -, many other risk factors are associated with fracture risk (2). These include clinical risk factors, the risk of falling, prevalent morphometric vertebral fractures, and secondary osteoporosis (3-6). After a clinical vertebral or non-vertebral fracture, patients are at increased risk for subsequent fractures. Patients presenting with fractures should therefore be screened to exclude diseases that can mimic osteoporosis, and possible causes of osteoporosis and contributory factors should be investigated (1-5).
Prevention and treatment of osteoporosis consists of nondrug, drug, and/or hormonal treatment. Diet, exercise, and cessation of smoking are the three main components of the nondrug treatment of osteoporosis. Available antiresorptive drug therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator. Strontium ranelate has both anabolic and antiresorptive properties. Intermittent administration of recombinant human parathyroid hormone has been shown to stimulate bone formation.
Teriparatide is an anabolic agent belonging to new class of antiosteoporosis drugs (7). In contrast to antiresorptive agents, these drugs stimulate bone formation, activating bone remodeling (7). Parathyroid hormone 1-34, teriparatide, is available in the United States and Europe for the treatment of severe osteoporosis in both men and women at a dose of 20 μg/day. The Turkish Social Security Institution (SGK) covers teriparatide therapy for patients with osteoporosis who have 2 osteoporotic fractures, who are older than 65 years, and who have a T-score of less than -4. Only endocrinologists can prescribe this drug in Turkey; other specialists caring for patients with osteoporosis must refer their patients to endocrinologists for teriparatide treatment.
Given the importance of identifying secondary contributors of osteoporosis in patients with fracture, and the advent of this new treatment for osteoporotic patients with fractures, we wish to describe the characteristics of patients referred to our clinic for osteoporosis treatment with teriparatide.
This prospectively planned, descriptive study was conducted in the outpatient clinic of the department of endocrinology and metabolism at Trabzon Kanuni Training and Research Hospital in Trabzon, Turkey. All patients who were referred for teriparatide treatment were recruited for the study.
Patients were evaluated for the clinical risk factors for osteoporosis, medical history, and medication. We recorded age, age at menopause, current or previous calcium and vitamin D supplementation, current or previous antiresorptive therapy, history of cigarette smoking, and alcohol intake. Physical examination was performed, and body weight and height were measured.
All patients underwent dual x-ray absorptiometry and plain, 2-sided thoracolumbar radiography. Laboratory examinations performed for all patients were as follows: kidney, liver, and thyroid function tests (blood urea nitrogen, creatinine, sodium, potassium, alanine aminotransferase, free tetraiodothyronine, thyroid-stimulating hormone), complete blood count, follicle-stimulating hormone, estradiol for women and total testosterone for men, calcium, phosphate, serum 25(OH) vitamin D, parathyroid hormone, and alkaline phosphatase. Additional tests were performed when needed.
We performed overnight dexamethasone suppression tests for suspected cases of Cushing’s syndrome. In patients with hypogonadism, magnetic resonance imaging of the hypophysis or/and ultrasonography of gonads (ovarian, scrotal) was performed when needed. Patients with primary hyperparathyroidism underwent 24-hour urinary calcium collection. Glomerular filtration rate was calculated when needed. Vitamin D deficiency was defined as a level of <20 ng/mL.
We used SPSS software (version 13.0; SPSS Inc., Chicago, IL) for statistical analyses. Only descriptive statistics were calculated.
Between December 2010 and April 2012, 63 women and 5 men were referred to our clinic for treatment with teriparatide. Fifty-two patients (76.5%) were referred by physiatrists, 14 (20.6%) by orthopedists, and 2 (2.9%) by internists. All patients had 2 or more fractures, and 28 (41.2%) had at least 1 systemic disease (Table 1).
In all, 29 (42.6%) patients had received previous treatment for osteoporosis: 20 (29.4%) had received bisphosphonates, 6 (8.8%) had received strontium ranelate, 2 (2.9%) had received calcitonin, and 1 (1.5%) had received calcitonin and bisphosphonate (Table 1). Of note, 116 of the 24 (66.7%) 24 patients receiving vitamin D supplementation (combined with calcium) still had vitamin D deficiency.
In all, 50 of the 68 patients (73.5%) were found to have 1 or more contributors to secondary osteoporosis (Table 2), many of which had been undetected until referral. Among the 18 patients found to have hyperthyroidism, only 3 already had a diagnosis of hyperthyroidism and were taking the antithyroid drug propylthiouracil; we diagnosed the remaining 15 cases. The diagnoses of hypogonadism (n=5) and hyperparathyroidism (n=1) also were newly established. Nine patients with hyperthyroidism had been taking antiresorptive treatment; only 3 of them had been diagnosed previously. One of the male patients with hypogonadism also had been taking antiresorptive therapy.
In this study, nearly three quarters of our osteoporotic patients with fracture had a secondary contributor to osteoporosis. In many cases, these contributors had not been previously identified.
In a study of 173 otherwise healthy women with osteoporosis, Tannenbaum and colleagues (4) identified secondary contributors to osteoporosis in 55 women (32%). Contributors to secondary osteoporosis in this study included hypercalciuria (9.8%), malabsorption (8.1%), hyperparathyroidism (6.9%), vitamin D deficiency (4.1%), exogenous hyperthyroidism (2.3%), Cushing’s disease (0.6%), and hypocalciuric hypercalcemia (0.6%). The authors underlined the importance of recognizing undiagnosed causes of osteoporosis (4). Of note, the presence of clinical fracture was ignored in this study, and only postmenopausal women with osteoporosis were included.
A study from Belgium evaluated 100 consecutive patients (73 women and 27 men) older than 50 years who presented with a clinical fracture (6). Overall, 27 patients had 34 known contributors to secondary osteoporosis, but 53 new contributors were detected in 50 patients. Among the overall contributors, 77% was similar to that found in our cohort, as is the fact that most of the new contributors were vitamin D deficiency (n=42). Other common contributors in this study were renal disorders (n=14), pulmonary disease (n=5), hyperthyroidism (n=3), and diabetes mellitus (type not indicated; n=5). Although Type 1 diabetes has been associated with osteoporosis, data conflict about the relationship with Type 2 diabetes (8). We did not include diabetes as a possible contributor to secondary osteoporosis because all of our diabetic patients had Type 2 disease.
The Belgian study also detected hypogonadism in men (6), which in our study had previously gone undetected. Women with hypogonadism are usually diagnosed earlier than men with the disorder, given that menstrual irregularities can be alarming. We detected hypogonadism only while searching for possible contributors to secondary osteoporosis. However, hypogonadism is one of the best characterized risk factors for osteoporosis in men (9, 10), and the 40% incidence of the disorder in men in our study is similar to that found by Bours and colleagues (42.5%) (11). In their study, the most common contributors overall were chronic obstructive pulmonary disease (10.4%), glucocorticoid use (8.5%), rheumatoid arthritis or systemic lupus (5.2%), and premature ovarian failure (4%).
The second most frequent contributor in our study was hyperthyroidism, similar to findings from other studies (4, 6, 11). Among 18 patients with the disorder, only 3 had a diagnosis of hyperthyroidism upon admission to our clinic. Hyperthyroidism, either exogenous or endogenous, is closely associated with a loss of bone mass and increased fracture risk. When adequate treatment is established, fracture risk declines (12). A recent review has advocated evaluating patients with subclinical hyperthyroidism for osteoporosis and treating in cases of reduced bone mass (13).
Primary hyperparathyroidism, chronic renal failure, chronic obstructive pulmonary disease, rheumatoid arthritis, and malnutrition are other well-known contributors to secondary osteoporosis (14), as is the use of warfarin, glucocorticoids, anticonvulsant drugs, heparin, gonadotropin-releasing hormone analogs, and cyclosporine (15). Data continue to emerge regarding a possible risk of secondary osteoporosis with the use of selective serotonin reuptake inhibitors and long-term proton pump inhibitor therapy (16,17), leading us to include such patients in our analysis.
In summary, most of the patients in our observational cohort had a contributor to secondary osteoporosis, many of which had previously gone undetected. Identifying and correcting these disorders is possible and might improve the treatment of osteoporosis and reduce the risk of subsequent fractures. We suggest that clinicians take a detailed history from patients who have severe osteoporosis and clinical fracture to screen for contributors to secondary osteoporosis.
Declaration of interest: None
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author a: IA drafted the manuscript and gave approval of the final version to be published. KE, MK, SA and MA substantially contributed to the acquisition and interpretation of data. EA critically revised the manuscript. Each author participated sufficiently in the work to take public responsibility for appropriate portions of the content. All authors read and approved the final manuscript.
1. Consensus Development Conference Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646-50.
2. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;843: 1.129.
3. Compston J, Cooper A, Cooper C, et al. Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Maturitas 2009;62:105-8.
4. Tannenbaum C, Clark J, Schwartzman K, et al. Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J. Clin. Endocrinol. Metab 2002;87:4431-7.
5. Kanis JA, McCloskey EV, Johansson H, et al. Case finding for the management of osteoporosis with FRAX--assessment and intervention thresholds for the UK. Osteoporos. Int 2008;19:1395-1408.
6. Dumitrescu B, van Helden S, ten Broeke R, et al. Evaluation of patients with a recent clinical fracture and osteoporosis, a multidisciplinary approach. BMC Musculoskelet. Disord 2008;9:109.
7. C.J. Rosen, J.P. Bilezikian, Clinical review 123: Anabolic therapy for osteoporosis. J. Clin. Endocrinol. Metab 2001;86:957-64.
8. I. Anaforoglu, A. Nar-Demirer, N. Bascil-Tutuncu, M.E. Ertorer, Prevalence of osteoporosis and factors affecting bone mineral density among postmenopausal Turkish women with type 2 diabetes. J. Diabetes. Complicat 2009;23:12-7.
9. N. Kelepouris, K.D. Harper, F. Gannon, F.S. Kaplan, J.G. Haddad, Severe osteoporosis in men. Ann. Intern. Med 1995;123:452-60.
10. J.A. Jackson, M. Kleerekoper, Osteoporosis in men: diagnosis, pathophysiology, and prevention. Medicine (Baltimore) 1990;69:137-52.
11. Bours SP, van Geel TA, Geusens PP, et al. Contributors to secondary osteoporosis and metabolic bone diseases in patients presenting with a clinical fracture. J. Clin. Endocrinol. Metab 2011;96:1360-7.
12. P. Vestergaard, L. Mosekilde, Hyperthyroidism, bone mineral, and fracture risk-a meta-analysis. Thyroid 2003;13:585-93.
13. B. Biondi, D.S. Cooper, The clinical significance of subclinical thyroid dysfunction. Endocr. Rev 2012;907214.
14. T. Miazgowski, M. Kleerekoper, D. Felsenberg, J.J. St?pán, P. Szulc, Secondary osteoporosis: endocrine and metabolic causes of bone mass deterioration. J Osteoporos 2012.
15. H.N. Rosen, Drugs that affect bone metabolism. http://www.uptodate.com/contents/drugs-that-affect-bone-metabolism. Accessed 2012.
16. N. Vakil, Prescribing proton pump inhibitors: is it time to pause and rethink? Drugs 2012;72:437-45.
17. Chau K, Atkinson SA, Taylor VH. Are selective serotonin reuptake inhibitors a secondary cause of low bone density? J. Osteoporos 2012;323061.