SECONDARY CAUSES OF OSTEOPOROSIS Nelson B. Watts, MD Bone Health and Osteoporosis Center Metabolic Bone Diseases and Mineral Disorders

SECONDARY CAUSES OF OSTEOPOROSIS Use of bone densitometry Secondary causes of bone loss Laboratory evaluation Calcium and vitamin D Bone turnover markers Lateral spine imaging with DXA

DEFINITION OF OSTEOPOROSIS A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the integration of two main features: bone density and bone quality. Normal Bone The “old” definition distinguished osteoporosis (in which the makeup of bone was normal) from osteomalacia (in which mineralization was clearly abnormal). The “modern” definition introduces the importance of bone quality (micro-architecture). Although this definition dates back to 1991, there is still no clinical test of bone quality. Thus, the clinically-relevant parts of the definition are bone mass and fractures. 2000 NIH Consensus Development Conference Osteoporotic Bone

WHO CRITERIA FOR POSTMENOPAUSAL OSTEOPOROSIS The T-score compares an individual’s BMD with the mean value for young normal individuals and expresses the difference as a standard deviation score. Kanis JA et al, J Bone Miner Res 1994;9:1137-1141 -2.5 and below Osteoporosis Between -1.0 to -2.5 Low bone mass (osteopenia) -1.0 and above Normal T-score Category

Kanis JA, et al. J Bone Miner Res 1994; 9:1137-1141 WHY THE WHO CHOSE T = -2.5 "When measurements are made at the hip alone, …the prevalence [of osteoporosis] is about one in five white women, comparable to the lifetime risk of a single osteoporotic fracture, such as a hip fracture.“ "Such a cutoff value identifies approximately 30% of postmenopausal women as having osteoporosis using measurements made at the spine, hip, or forearm. This is approximately equivalent to the lifetime risk of fracture at these sites." In developing the WHO criteria it was appealing to identify the same number of individuals with osteoporosis as would eventually have an osteoporotic fracture (realize that these would not necessarily be the same individuals). Using the T=-2.5 threshold, the prevalence of osteoporosis in postmenopausal women approximately equals the lifetime fracture risk for a a 50-year-old Caucasian women. See next slide. Kanis JA, et al. J Bone Miner Res 1994; 9:1137-1141

BONE DENSITY MEASUREMENTS AT PERIPHERAL SITES QUS DXA pQCT ADVANTAGES Portable Less expensive than central DXA Ultrasound does not involve radiation LIMITATIONS Less predictive for hip fracture than hip measurement Cannot be used for diagnosis with WHO criteria Cannot be used for monitoring (sites less likely to change)

PREVALENCE OF OSTEOPOROSIS AND LIFETIME FRACTURE RISK IN WHITE WOMEN 1 2 Percent Note that at a T-score = -2.5 Lifetime fracture risk is close to the prevalence at each site and combination of all three. For example, 16% of postmenopausal Caucasian women have osteoporosis at the femoral neck which is similar to the 17.5% lifetime risk of hip fracture for a 50-year-old Caucasian woman. This methodology has implications for the future approach for other groups: men, younger women, other racial groups to be discussed later in this lecture. 1. Melton LJ III, et al. J Bone Miner Res 1995;10:175 2. Melton LJ III, et al. J Bone Miner Res 1992;7:1005

PREVALENCE OF OSTEOPOROSIS VARIES BY SITE AND METHOD NORA Study, 200,160 ambulatory women age 50 and older Missed 55% Percent of subjects 2.5 SD or more below young adult mean 66% 84% 90% *Estimated from NAHNES III Siris E et al, JAMA 2001;286:2815-2822

AGE DEPENDENCE OF T-SCORES Data from manufacturers' data bases T-score Age (years) Faulkner KG et al. J Clin Densitom 1999;2:343

WHO CRITERIA Apply only to postmenopausal Caucasian women not men, younger women, other ethnic groups Apply only PA spine, hip and forearm DXA not lateral spine, heel, finger, etc Apply only for central DXA not peripheral DXA, QCT, QUS, etc. Points out the limitation of the WHO criteria. Limited by patient population, site and technology.

RISK FACTORS FOR OSTEOPOROSIS FEMALE OLDER AGE EARLY MENOPAUSE FAMILY HISTORY FAIR SKIN NULLIPARITY SLENDER BUILD LOW CALCIUM INTAKE SMOKING INACTIVITY

RISK FACTORS AND LOW BMD IMPACT Trial ~7,000 women in 21 countries without known osteoporosis had BMD testing and risk factor assessment 36% did have osteoporosis 48% had no risk factors 52% had one or more risk factors 64% did not have osteoporosis 67% had no risk factors 33% had one or more risk factors ~50% of patients with osteoporosis ..did not have risk factors ~50% of patients with risk factors did ..not have osteoporosis Watts NB et al, Arthritis Rheum 2001;44:S256

WHO SHOULD HAVE A BONE DENSITY TEST? U.S. Preventive Services Task Force Women 65 years of age and older [should] be screened routinely for osteoporosis Routine screening [should] begin at 60 years of age for women at increased risk for osteoporotic fractures Low body weight (<70 kg) Lack of estrogen Possibly other risk factors No recommendation for or against screening younger women at high risk US PSTF, Ann Intern Med 2002;137:526-528

WHO SHOULD HAVE A BONE DENSITY TEST? Number Needed to Screen Number Needed to Treat Fracture Type Fracture Type Age Age Nelson HD et al, Ann Intern Med 2002;137;529-541

WHO SHOULD HAVE A BONE DENSITY TEST? Society Providing Recommendation Patient category US PSTF NOF AACE ISCD Women  age 65 Yes Women 60-65 with risk factors Women  60 with risk factors Insufficient data Men  age 70 Not addressed Younger men with risk factors ISCD OsteoFLASH, www.iscd.org

FDA-APPROVED MEDICATIONS INDICATIONS Postmenopausal Osteoporosis Glucocorticoid-induced Osteoporosis Men Drug Prevention Treatment Estrogen  Calcitonin (Miacalcin®, Fortical®) Raloxifene (Evista®) Ibandronate (Boniva®) Alendronate (Fosamax®) Risedronate (Actonel®) Zoledronic acid (Reclast®) Teriparatide (Forteo®) Paget’s dose: Fosamax 40 mg/day x 6 mo., Actonel 30 mg/day x 2 mo.

FDA-APPROVED MEDICATIONS EVIDENCE FOR FRACTURE REDUCTION Drug Vertebral Fracture Nonvertebral Fracture Hip Fracture Calcitonin (Miacalcin®, Fortical®)  No effect demonstrated Raloxifene (Evista®) Ibandronate (Boniva®) Alendronate (Fosamax®)  Risedronate (Actonel®) Zoledronic acid (Reclast®) Teriparatide (Forteo®) Evidence for effect but not an FDA-approved indication

NOF TREATMENT GUIDELINES 2008 www.nof.org

NOF GUIDE -- 2008 Postmenopausal women and men age 50 and older presenting with the following should be treated: A hip or vertebral (clinical or morphometric) fracture BMD T-score ≤ -2.5 at the femoral neck, total hip or spine after appropriate evaluation to exclude secondary causes Low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip or spine) AND 10-year probability of hip fracture ≥3% or 10-year probability of any major osteoporosis-related fracture* ≥20% based on the US-adapted WHO algorithm *Hip, humerus, forearm or clinical vertebral fracture

NOF GUIDELINES 2008 After exclusion of secondary cause, treat postmenopausal women and men age 50 and older who have… T-scores between -1.0 and -2.5 A fracture of the hip or vertebra (clinical or morphometric) T-score -2.5 or below in the femoral neck, total hip or spine 10-year risk ≥3% for hip fracture or ≥20% for major osteoporotic fractures based on FRAX™ model

www.shef.ac.uk/FRAX

www.shef.ac.uk/FRAX

FN T-score -2.4, no risk factors Mary Smith, 66.8 years old Wt. 140 lbs., Ht 64 in. FN T-score -2.4, no risk factors www.shef.ac.uk/FRAX

EVALUATION OF PATIENTS WITH OSTEOPOROSIS Just because a woman is postmenopausal and has osteoporosis doesn’t mean that she has postmenopausal osteoporosis Failure to identify underlying disorders may result in inadequate or inappropriate treatment

SOME CAUSES OF SECONDARY OSTEOPOROSIS IN ADULTS Endocrine Disease or Metabolic Causes Nutritional Conditions Drugs Disorders of Collagen Metabolism Other Hypogonadism Hypercalciuria Hyperthyroidism Hyperparathyroidism Cushing’s syndrome Acromegaly Growth hormone deficiency Vitamin D deficiency Calcium deficiency Vit. B12 deficiency Weight loss Malabsorption Gastric surgery Anorexia nervosa Chronic liver disease Alcoholism Malnutrition Prolonged TPN Glucocorticoids Anti-epilepsy drugs Excess thyroid hormone Depo-Provera GnRH agonists Aromatase inhibitors Heparin Osteogenesis imperfecta Homocystinuria Ehlers-Danlos syndrome Marfan Rheumatoid arthritis Inflammatory bowel disease COPD Organ transplantation Immobilization Multiple myeloma Some cancers Renal tubular acidosis Gaucher’s disease Mastocytosis Thalassemia Adapted from Hodgson SF and Watts NB, AACE Guidelines on Osteoporosis, www.aace.com

ENDOCRINE AND METABOLIC DISEASES ASSOCIATED WITH OSTEOPOROSIS Hypogonadism Hypercalciuria Hyperthyroidism Hyperparathyroidism Cushing’s syndrome Acromegaly Growth hormone deficiency

NUTRITIONAL CONDITIONS ASSOCIATED WITH OSTEOPOROSIS Vitamin D deficiency Calcium deficiency Vitamin B12 deficiency Weight loss Malabsorption Gastric surgery Anorexia nervosa Chronic liver disease Alcoholism Malnutrition Prolonged TPN

DRUGS ASSOCIATED WITH OSTEOPOROSIS Glucocorticoids Anti-epilepsy drugs Thyroid hormone (supraphysiologic doses) Depo-Provera GnRH agonists Aromatase inhibitors TZDs SSRIs PPIs

DISORDERS OF COLLAGEN METABOLISM Osteogenesis imperfecta Homocystinuria Ehlers-Danlos syndrome Marfan syndrome

OSTEOGENESIS IMPERFECTA Type I Autosomal dominant inheritance Decreased production of type I procollagen; substitution for glycine in triple helix of 1(I) Normal stature Little or no deformity Blue sclerae Hearing loss in 50% Teeth are usually normal Histomorphometry: increased cortical osteocytes, woven bone, thin collagen bundles

OSTEOGENESIS IMPERFECTA Type IV Autosomal dominant inheritance Point mutation in 2(I) chain Normal sclerae Mild to moderate deformity Variable short stature Hearing loss in some Dentogenesis imperfecta is common

OTHER CAUSES OF LOW BONE MASS Rheumatoid arthritis Inflammatory bowel disease COPD Organ transplantation Immobilization Multiple myeloma Some cancers Renal tubular acidosis Gaucher’s disease Mastocytosis Thalassemia

How often are secondary causes found?

SECONDARY CAUSES OF OSTEOPOROSIS Post-menopausal women over age 65 BMD T-score -2.5 or below (n=664) History of known medications or diseases affecting bone and mineral metabolism (n=355) No previous known contributors to osteoporosis based on past medical history (n=309) Ineligible subjects Incomplete laboratory testing (n=136) Eligible subjects Complete battery of laboratory tests available (n=173) Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437

SECONDARY CAUSES OF OSTEOPOROSIS Patients with at least 1 new diagnosis (n=84) 48.6% Vitamin D deficiency, <20 ng/mL (n=35) 20.2% Hypercalciuria 9.8% Renal (n=7) Idiopathic (n=6) Undefined (n=4) Malabsorption 8.1% Relative calcium malabsorption (n=11) Celiac sprue (n=3) Hyperparathyroidism 6.9% Primary (n=1) Secondary (n=11) Exogenous hyperthyroidism (n=4) 2.3% Cushing’s disease (n=1) 0.6% Hypocalciuric hypercalcemia (n=1) 0.6% Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437

LABORATORY EVALUATION FOR OSTEOPOROSIS Abnormal 24-h urine calcium for all 39/173 Serum 25-OH vitamin D for all 35/173 Serum calcium for all 3/173 Serum TSH for all on replacement 4/25 This strategy finds 98% of cases, costs $116 per patient screened, $332 per case found Tannenbaum C et al, J Clin Endocrinol Metab 2002;87:4431-4437

VITAMIN D STATUS Best reflected by serum 25-hydroxyvitamin D levels Lab reference range is 20-100 ng/mL Minimum desirable level is 30 ng/mL (80 nmol/L) Reasonable range is 30 to 60 ng/mL (80 to 150 nmol/L)

VITAMIN D REDUCES RISK OF FALLING Meta-Analysis Bischoff-Ferrari HA et al. JAMA 2004;291:1999-2006

VITAMIN D REDUCES FRACTURES AND MAY REDUCE MORTALITY Vitamin D 100,000 IU Q 4 months or placebo N=2037 men and 649 women ages 65-85 Fractures (hip, wrist, forearm, vertebra) Survival OR 0.78 (0.61,0.99) OR 0.88 (0.74,1.06)) Trivedi DP et al, BMJ 2003;326-469-475

MOST OF US WILL BENEFIT FROM A VITAMIN D SUPPLEMENT Vitamin D has important skeletal and extra-skeletal effects Adequate 25-hydroxyvitamin D level is ≥30 ng/dL Vitamin D deficiency is common Most patients require 1,000-2,000 IU vitamin D per day to achieve an adequate level “Safe upper limit” is 2,000 IU per day Supplements of 1,000 IU tablets are now widely available (1,000-2,000 IU daily Rx 50,000 IU ergocalciferol may be required (weekly, every other week)

OPTIMAL CALCIUM INTAKE 1200 mg daily for adults age 50 and older TOTAL FROM ALL SOURCES Average calcium from diet: Women 50 and older : ~500 mg daily Men 50 and older: ~600 mg daily Most people need a calcium supplement of 700 to 1000 mg daily. Many people are taking too much.

24-HOUR URINE CALCIUM Lab reference range 100-300 mg/day Typical is 2-3 mg/kg/day Upper limit of “normal” is 4 mg/kg/day Wt 100 kg, normal up to 400 mg/day Wt 50 kg, normal up to 200 mg/day Low urine calcium = low intake or malabsorption High urine calcium = high intake or calcium wasting Must be collected when vitamin D is adequate and calcium intake is within target of 1200-1500 mg daily

LABORATORY EVALUATION FOR OSTEOPOROSIS CBC Chemistry panel and phosphorus 25-hydroxyvitamin D 24-hour urine for calcium and creatinine If patient is male, serum testosterone (total and free) Other studies if indicated by history, physical findings or initial laboratory results

BIOCHEMICAL MARKERS OF BONE TURNOVER Enzymes (alkaline phosphatase, acid phosphatase) Degradation products (hydroxyproline, collagen cross links) Byproducts (osteocalcin, procollagen I extension peptides)

COLLAGEN CROSS LINKS N-TELOPEPTIDE C-TELOPEPTIDE HELICAL REGION REGION CTx Pyr NTx Dpd Watts NB. Clin Chem 1999;45:1359-1368

BMD AND MARKERS PREDICT HIP FRACTURE THE EPIDOS STUDY 6 CTX Free DPD 2.2 1.9 High Marker 4.8 4.1 Both 5 4 Odds Ratio 2.7 3 2 1 Low Hip BMD Garnero P et al, J Bone Miner Res 1996;11:1531

NOT EVERYONE WITH OSTEOPOROSIS HAS ABNORMAL BONE TURNOVER 89 Elderly Women with Osteoporosis Pyr Dpd NTx Garnero P et al, J Clin Endocrinol Metab 1994;79:1693

URINE NTX Remodeling has diurnal variation: need second morning fasting urine or fasting blood Urine sample may be preferred for logistical reasons Reference range Ostex Mayo Quest Premenopausal women 5-65 0-64 10-110 Men 3-51 11-103 Postmenopausal women NA 0-130 Target: at or below the median value for premenopausal women (30 nmol BCE/mmol creatinine)* *de Papp AE et al, Bone 2007;40:1222-1230

CLINICAL USES FOR BONE TURNOVER MARKERS Patient with borderline low BMD who is not a treatment candidate: when to test again Patient with low BMD who has no other risk factors: when to treat Patient on antiresorptive treatment who has bone loss or fracture: is the medication being absorbed and is it working? Patient on anabolic therapy: is medication working?

REMINDER Osteoporosis can be diagnosed based on the presence or history of an osteoporotic fracture; however, a fracture is not required for diagnosis

LATERAL SPINE IMAGING WITH DXA Done with current DXA equipment at time of DXA visit (convenient) Small amount of radiation Good at visualizing T4-L4 and identifying moderate and severe fractures Not good at visualizing upper thoracic vertebrae or mild compression fractures

IMPORTANCE OF RECOGNIZING VERTEBRAL DEFORMITIES 482 women being screened for osteoporosis studies. All had BMD and lateral spine imaging. Osteoporosis was defined as either T-2.5 or below OR a vertebral deformity. 32% T –2.5 or below 57% T above –2.5 No vertebral deformity 11% T above -2.5 but vertebral deformity 26% of those with “osteoporosis” had T-scores above –2.5 but had one or more vertebral deformities Greenspan SL et al, J Clin Densitom 2001;4:373-380

USING DXA EQUIPMENT FOR VERTEBRAL FRACTURE ASSESSMENT CPT code 77082, reimbursement ~$30 Vertebral fracture assessment (VFA) with DXA equipment is useful for screening patients with “osteopenia” (to decide when to treat) or osteoporosis (for selection of therapeutic agent) Utility for monitoring not clear If vertebral fractures are strongly suspected, get x-rays

FOR PATIENTS WITH FRACTURE Remember: not all fractures are due to osteoporosis. Consider bone scan if there is equivocal fracture or if fracture might be remote Consider MRI or biopsy if fracture might be due to metastatic carcinoma Consider MRI if there is question of lateral or posterior displacement

ILIAC CREST BONE BIOPSY Patients with unusual features of osteoporosis men young women patients with very low bone mass patients who have fragility fractures but normal bone mass Patients failing conventional therapy

EVALUATION OF PATIENTS WITH OSTEOPOROSIS Use central DXA for testing, women 65 and older without risk factors and younger postmenopausal women with risk factors All patients with osteoporosis should have lab workup for secondary causes Give the right amount of calcium and plenty of vitamin D Bone turnover markers have a limited role Lateral spine imaging with DXA should be done in selected patients

SECONDARY CAUSES OF OSTEOPOROSIS Questions or comments? WILL YOUR BONES LAST AS LONG AS YOU DO?