IDIOPATHIC OSTEOPOROSIS IN PREMENOPAUSAL WOMEN Elizabeth Shane, M.D. Columbia University, College of Physicians & Surgeons USA SIGNIFICANCE OF THE TOPIC Although idiopathic osteoporosis (IOP) in premenopausal women is rare, such patients often present challenges in diagnosis and management. LEARNING OBJECTIVES To understand the significance and causes of low BMD in premenopausal women To understand the microstructural, remodeling and bone material property characteristics of bone in women with IOP To understand the principles of management of osteoporosis in premenopausal women with secondary osteoporosis and IOP DIAGNOSIS AND ETIOLOGY OF OSTEOPOROSIS IN PREMENOPAUSAL WOMEN In postmenopausal women, osteoporosis is defined as a BMD of the spine, hip, or forearm more than 2.5 SD below the young adult mean (T-score -2.5), with or without the presence of a low trauma fracture; osteopenia refers to T scores between -1.0 and -2.5. In premenopausal women, T scores should not be used to categorize BMD, the term osteopenia should not be used at all, and the term osteoporosis should be used judiciously. Z scores, which compare a young woman s BMD to the mean of an age-, gender-, and ethnicitymatched reference population, should be used instead of T scores to categorize BMD measurements. Based on the definition of a Z-score, which encompasses 95% of the normal population, 2.5% of premenopausal women will have a Z-score < 2.0. A Z score that is -2.0 should be designated low bone density or below expected for age. The term osteoporosis should be avoided in premenopausal women with isolated low BMD measurements, because the degree to which isolated low BMD measurements predict shortterm (5-10 year) fracture incidence in young women is unknown. In addition, the clinical significance of isolated low BMD measurements is uncertain. Some premenopausal women with small skeletons may appear to have low BMD, because DXA scanners cannot distinguish between small bones and less dense bones. Thin premenopausal women may have low BMD because their skeletons are adapted to carrying lower loads. They may also have low BMD because they have genetically determined low peak bone mass. It is generally assumed that such women have normal bone quality (normal trabecular and cortical volumetric BMD and microarchitecture and stiffness or strength), although there are no data to support this assumption. On the other hand, during adolescence, certain life style choices (excessive alcohol, tobacco exposure, low calcium intake, physical inactivity) or an underlying illness or exposure to certain medications (glucocorticoids, Depo-Provera) may interfere with peak bone mass acquisition. Such secondary causes of osteoporosis, which may also cause excessive bone loss after adolescence, may be associated with abnormal bone quality, although again there are few data. Lactation is associated with losses of 3-10% at the spine and hip over the first 3-6 months with recovery after weaning over the next 12-18 months. Therefore, BMD measurements should not 1
performed for at least a year after pregnancy or lactation, during this period of transient loss and recovery. Routine BMD screening of premenopausal or perimenopausal women is not recommended unless there is a history of fragility fracture(s), or conditions or medications associated with low bone mass or bone loss (estrogen deficiency, glucocorticoids, etc). Premenopausal women with a low trauma fracture or Z score -2.0 should have a thorough history, physical examination and laboratory evaluation to identify potential secondary causes of bone loss, such as renal or liver disease, hyperthyroidism, hyperparathyroidism, Cushing s syndrome, early menopause, other disorders associated with estrogen deficiency, such as anorexia, celiac disease and other forms of malabsorption, idiopathic hypercalciuria, or connective tissue disorders. Table 1: Secondary causes of osteoporosis in premenopausal women Anorexia nervosa Gastrointestinal malabsorption (eg. celiac disease, postoperative states) Vitamin D and/or calcium deficiency Hyperthyroidism Hyperparathyroidism Cushing s syndrome Hypogonadism Hypercalciuria Rheumatoid arthritis and other inflammatory conditions Alcoholism Renal Disease Liver disease Osteogenesis imperfecta Marfan s syndrome Homocystinuria Medications Glucocorticoids Immunosuppressants (cyclosporine) Antiseizure medications (particularly phenobarbital and phenytoin) GnRH agonists (when used to suppress ovulation) Heparin Cancer chemotherapy Depot medroxyprogesterone acetate Excess thyroid hormone Table 2. Guidelines for BMD Testing in Premenopausal Women History of fragility fracture Diseases or conditions associated with low bone mass or bone loss o Premenopausal estrogen deficiency (e.g., anorexia nervosa, hyperprolactinemia, prolonged amenorrhea) o Chronic obstructive pulmonary disease o Cystic fibrosis o Hyperparathyroidism o Rheumatoid arthritis o Inflammatory bowel disease 2
o Celiac disease Medications that cause bone loss o Glucocorticoids o Depot progesterone o GnRH agonists o Aromatase inhibitors o Antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, valproate) If pharmacologic therapy of osteoporosis is being considered Being monitored for effectiveness of pharmacologic therapy for osteoporosis IDIOPATHIC OSTEOPOROSIS IN PREMENOPAUSAL WOMEN Premenopausal women with no identifiable etiology after extensive evaluation for secondary causes are said to have idiopathic osteoporosis (IOP). Idiopathic osteoporosis primarily affects Caucasians, men and women equally. Presentation may occur during pregnancy or lactation. The mean age at diagnosis is in the mid-thirties. Fractures are usually multiple, occurring over a 5 to 10 year period. Abnormalities of osteoblast function and decreased IGF-1 have been found in some studies, but not others. In a recent bone biopsy study of women with IOP, both those with fractures and those with Z scores 2.0 but no fractures had evidence of low volumetric BMD of the hip and spine (by central QCT), distal radius and tibia (by high resolution peripheral QCT or HR-pQCT) and iliac crest bone biopsies (by microct). In addition, both groups had comparable microarchitectural disruption and reduced estimated strength (by finite element analysis or FEA). In addition, both groups of affected women had increased marrow fat (independent of bone volume fraction), reduced bone mineralization density distribution (BMDD by quantitative backscattered electron imaging) and abnormal bone matrix (by Fourier transform infrared spectroscopy). Bone turnover was heterogeneous, but those in the lowest tertile of bone turnover had the most marked deficits in volumetric BMD, microarchitecture and strength. Serum IGF-1 was higher in the women in the lowest tertile of bone formation rate, suggesting that they may have IGF-1 resistance at the osteoblast level. There were virtually no differences between premenopausal women with IOP who had fractures and those with only low BMD. However, whether these women reflect the larger population of premenopausal women with low BMD is unknown and the lack of detectable differences may represent ascertainment bias, as women with a family history of osteoporosis or some other reason to suspect poor bone health may have been more likely to participate. MANAGEMENT There are no official guidelines for management of premenopausal women with low bone mass or osteoporosis. Lifestyle modifications should be encouraged for all women with low bone mass since peak bone mass may improve well into the fourth decade. The following should be encouraged: adequate calcium intake (1000 1200 mg elemental calcium daily); adequate vitamin D intake (400-800 IU vitamin D3 daily) or sufficient to maintain serum 25-OHD levels above 20-30 ng/ml; regular physical activity, particularly weight-bearing exercise; cessation of smoking; avoid excessive dieting and maintain normal body weight; avoid excess alcohol, caffeine and phosphorus containing drinks. A recent study of 16 premenopausal women with IOP treated only with increased dietary calcium and physical activity revealed small but significant increases in lumbar spine and femoral neck BMD after 2 or 3 years and no new fractures. When a secondary cause of osteoporosis is detected in premenopausal women, treatment should be targeted to that disease or abnormality. Examples of specific approaches that have been shown to lead to increases in BMD include: 3
Institution of a gluten-free diet in celiac disease Parathyroidectomy in patients with primary hyperparathyroidism Discontinuation of medroxyprogesterone acetate Oral contraceptives for women with oligo- or amenorrhea, on gonadotropin-releasing hormone (GnRH) therapy with perimenopausal bone loss Pharmacologic therapy should be avoided unless the patient is losing bone or fracturing. Selective estrogen receptor modulators (SERMs) such as raloxifene should not be used in menstruating women as they block estrogen action on bone, leading to further bone loss. Bisphosphonates carry a Category C rating for safety in pregnancy as they cross the placenta and accumulate in fetal bones in an experimental rat model. While they are probably safe, their long half-life in bone makes their use in reproductive age women a concern. In premenopausal women without fractures or known secondary causes for fractures, bisphosphonates are generally not indicated. Teriparatide has been shown to prevent bone loss in premenopausal women on GnRH agonists for endometriosis, to increase BMD in premenopausal women with GIOP, and with IOP. Teriparatide has the advantage of not being retained in the skeleton but whether its effects dissipate after cessation, as is seen in postmenopausal women or men, is unknown. Aggressive therapy with anti-osteoporosis agents may be necessary for women with glucocorticoid-induced osteoporosis. However, the 2010 American College of Rheumatology guidelines do not recommend pharmacologic therapy for prevention and treatment of glucocorticoid-induced osteoporosis patients under age 50, unless they have a history of spine or hip fracture and have taken or will be taking at least 7.5 mg of prednisone or equivalent daily for 90 days. Premenopausal women receiving chemotherapy for breast cancer represent another group at risk for rapid bone loss, primarily related to induction of premature menopause. Prospective studies demonstrate bone loss at 1 year of 4 8% in the spine and 2 4% at the hip in premenopausal women who become menopausal after receiving adjuvant chemotherapy. Intravenous bisphosphonates prevent bone loss in premenopausal women with chemotherapyinduced amenorrhea. Premenopausal women with osteogenesis imperfecta (OI) can be treated with either oral alendronate or intravenous pamidronate. In our recent pilot study of teriparatide in 21 premenopausal women with IOP, there were large and highly significant increases (~10%) in lumbar spine BMD, with smaller but also significant increases at the femoral neck and total hip, and no change at the radius. Teriparatide was also associated with marked improvements in trabecular volumetric BMD and microarchitecture and cortical thickness on iliac crest bone biopsies. About 20% of the women, however, did not respond (no change in BMD at any site). The nonresponsive women had markedly lower bone turnover at baseline, based on serum bone turnover markers and lower bone formation rate on iliac crest bone biopsies. They also had significantly These women also had smaller and delayed rises in serum P1NP and C-telopeptide during teriparatide therapy. We are currently beginning a new federally funded study of teriparatide in premenopausal women with IOP to confirm these preliminary observations and assess the mechanisms for the 4
lack of responsiveness in premenopausal women with low turnover IOP. We would welcome referrals to this study. To refer patients, please contact: Elizabeth Shane, MD at es54@columbia.edu Adi Cohen, MD at ac1044@columbia.edu Polly Young, MPH at pc2403@columbia.edu SUGGESTED REFERENCES 1. Peris P, Guanabens N, Martinez de Osaba MJ, Monegal A, Alvarez L, Pons F, Ros I, Cerda D, Munoz-Gomez J 2002 Clinical characteristics and etiologic factors of premenopausal osteoporosis in a group of Spanish women. Semin Arthritis Rheum 32(1):64-70 2. Peris P, Monegal A, Martinez MA, Moll C, Pons F, Guanabens N 2007 Bone mineral density evolution in young premenopausal women with idiopathic osteoporosis. Clin Rheumatol 26(6):958-61. 3. Cohen A, Fleischer J, Freeby MJ, McMahon DJ, Irani D, Shane E. Clinical characteristics and medication use among premenopausal women with osteoporosis and low BMD: the experience of an osteoporosis referral center. J Womens Health (Larchmt), Jan-Feb; 18(1):79-84, 2009 PMID 19132880 4. Cohen A, Liu XS, Stein EM, McMahon DJ, Rogers HF, LeMaster J, Recker RR, Lappe JM, Guo XE, Shane E. Bone Microarchitecture and stiffness in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. Nov; 94(11):4351-4360, 2009. PMID: 19837923 5. Cohen A, Recker RR, Lappe J, Dempster DW, Cremers S, McMahon DJ, Stein EM, Fleischer J, Rosen CJ, Rogers HF, Staron RB, LeMaster J, Shane E. Premenopausal women with idiopathic low trauma fractures and/or low bone mineral density. Osteoporos Int. 2011 Mar 2. [Epub ahead of print] 6. Cohen A, Dempster DW, Recker RR, Zhou H, Wirth AJ, van Lenthe, GH, Kohler T, Müller R, Stein EM, Rosen CJ, Nickolas TL, Rogers HF, Staron RB, LeMaster J, Shane E. Abnormal bone microarchitecture and evidence of osteoblast dysfunction in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. 2011 Oct;96(10):3095-105. Epub 2011 Aug 10 5