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Osteoporosis     RX  |  Causes  |  LAB  |  Male Osteoporosis  | Anabolic Rx for Osteoporosis  2007 | Osteoporosis Biphosphonates 2010        bisphosphonate20110223JAMA.pdf

Osteopenia  |  Osteoporosis (Mayo Clinic May 2006)   |  National Osteoporosis Foundation  |  KP Osteoporosis National Guidelines 2006

General Interventions Calcium - At least 1,000 mg per day is recommended; 1,500 mg per day is recommended for women age 50 and older who are not on estrogen. Vitamin D - Persons deficient in vitamin D (especially the elderly) should receive at least 400 IU per day. (See Vitamin D Deficiency article) Exercise - Regular weight-bearing or "muscle-building" exercise can help prevent osteoporosis. Don't Smoke - Smokers are at greater risk of hip fractures; all members should be strongly encouraged to quit smoking. Hormone Replacement Therapy  - Premarin 0.625 mg (higher risk for breast cancer, heart disease, thrombosis) or Evista/ Raloxifene 60 mg daily (Selective Estrogen-Receptor Modulator) as indicated. Oral Biphosphonate -   Alendronate/ Fosamax 10 mg daily or 70 mg weekly or   Risedronate/ Actonel  5 mg/day or 35 mg weekly (JAMA. Oct.13, 1999;282:1344-1352 Steven T. Harris)   Etidronate/Didronel 200 mg/day x 6 months.   Ibandronate /Boniva 2.5 mg (oral tablet) once daily or 150 mg tablet monthly. IV Biphosphonates Aredia/Pamidronate   30 mg IV once every 3 months or 90 mg IV over 2-3 hrs q 6 months    Zometa (Zoledronic Acid)   1 mg IV given once every 3 months, 2 mg IV once every 6 months, or 4 mg IV once every 12 months  (max 4 mg) given as a single dose infused over no less than 15 minutes. *  Watch for potential jaw osteonecrosis problem, especially in cancer patients with IV biphosphanates Rx. Reclast (Zoledronic acid) Once-yearly   5 mg IV infusion over 15 minute during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures.   NEJM May 3, 2007 (Horizon Study) Subc  Prolia (Denosumab) 60 mg subc every 6 months   - Prolia® helps stop the development of bone-removing cells before they can reach the bones and cause damage.   Prolia® is a prescription medicine used to treat osteoporosis (thinning and weakening of bone) in women after menopause who: Have an increased risk for fractures (broken bones). Cannot use another osteoporosis medicine or other osteoporosis medicines did not work well. Second-Line Therapies  of Osteoporosis for Women Second-line therapies are used when first-line agents are contraindicated or cannot be tolerated. The following second-line therapies have not been shown to significantly reduce nonvertebral fractures of the hip or wrist, however. As a result, consider consultation with a specialist before initiating therapy with calcitonin (Miacalcin), raloxifene (Evista) or etidronate. Intolerance to Oral Diphosphate Rx Pamidronate (Aredia) iv infusion: 60 mg or 90 mg iv over 4 hours every 3 to 6 months Ibandronate  (Boniva) iv push: 3mg iv push over 15 to 30 seconds every 3 months Zoledronic acid (Reclast or Zometa) iv infusion: 5mg iv over 15 minutes yearly Teriparitide (FORTEO) - Recombinant human PTH  20 mcg subc once daily    - stimulates new bone formation by preferential stimulation of osteoblastic activity over osteoclastic activity.   * Warning:  Please be sure the patient has adequate Vit. D level and is on Calcium supplement before taking Fosamax, Actonel type medications. 1. Musculoskletal Pain  from Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa)   - REF:  http://www.fda.gov/cder/drug/InfoSheets/HCP/bisphosphonatesHCP.htm   FDA ALERT [1/7/2008]: FDA is highlighting the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonate. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown. This severe musculoskeletal pain is in contrast to the acute phase response characterized by fever, chills, bone pain, myalgias, and arthralgias that sometimes accompanies initial administration of intravenous bisphosphonates and may occur with initial exposure to once-weekly or once-monthly doses of oral bisphosphonates. The symptoms related to the acute phase response tend to resolve within several days with continued drug use. Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. This information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.  2. Use of Alendronate (Fosamax) and Risk of Incident Atrial Fibrillation in Women.     -  REF: Arch Intern Med. April 28,2008;168(8):826-831  and  http://www.fda.gov/Cder/Drug/early_comm/bisphosphonates.htm   Methods:   We studied alendronate sodium ever use in relation to the risk of incident AF in women in a clinical practice setting. This population-based case-control study was conducted at Group Health, an integrated health care delivery system in Washington State. We identified 719 women with confirmed incident AF between October 1, 2001, and December 31, 2004, and 966 female control subjects without AF, selected at random from the Group Health enrollment and frequency matched on age, presence or absence of treated hypertension, and calendar year. Results: More AF case patients than controls had ever used alendronate (6.5% [n = 47] vs 4.1% [n = 40]; P = .03). Compared with never use of any bisphosphonate, ever use of alendronate was associated with a higher risk of incident AF (odds ratio, 1.86; 95% confidence interval, 1.09-3.15) after adjustment for the matching variables, a diagnosis of osteoporosis, and a history of cardiovascular disease. Based on the population-attributable fraction, we estimated that 3% of incident AF in this population might be explained by alendronate use. Conclusion: Ever use of alendronate was associated with an increased risk of incident AF in clinical practice. Calcitonin (Calcimar) 1 nasal spray daily (200 IU), or 100 IU Subc daily for osteoporosis or Calcitonin (Fortical, Miacalcin, Calcimar) 1 nasal spray daily (200 IU) Synthetic Parathyroid Hormone (PTH) - Teriparatide  (FORTEO) 20 mcg once daily subc. injection into the thigh or abdominal wall. See Anabolic Rx for steoporosis  2007 Experimental drugs: - Once-yearly bisphosphonate Zoledronic acid IV infusion - Delayed-release bisphosphonate Ibandronate  (Boniva) given q 3-4 weeks. - Nitrates  intermittent dose (Univ. of Toronto  Dr. Sophie Jamal) - Ultra-low dose estradiol transdermal patch 0.014 mg/daily Second-Line Therapies  of Osteoporosis for Women Second-line therapies are used when first-line agents are contraindicated or cannot be tolerated. The following second-line therapies have not been shown to significantly reduce nonvertebral fractures of the hip or wrist, however. As a result, consider consultation with a specialist before initiating therapy with calcitonin (Miacalcin), raloxifene (Evista) or etidronate. Intolerance to Oral Diphosphate Rx Pamidronate (Aredia) iv infusion: 60 mg or 90 mg iv over 4 hours every 3 to 6 months Ibandronate  (Boniva) iv push: 3mg iv push over 15 to 30 seconds every 3 months Zoledronic acid (Reclast or Zometa) iv infusion: 5mg iv over 15 minutes yearly Teriparitide (FORTEO) - Recombinant human PTH (1-34) Neer et al. (NEJM May 2001) 1637 women randomly assigned to receive placebo or SC PTH 20 or 40µg/d for a mean 21months study period (all received 1000mg calcium and 400-1200IU vitamin D) Increased BMD 9-13% spine, 3-5% femoral neck Reduced risk of new vertebral fractures by 65% and 69% Reduced risk of nonvertebral fractures by 35% and 40% Side Effects Nausea, headache High dose long term therapy associated with osteosarcoma in rats Avoid in patients with preexisting hypercalcemia Consider checking calcium 16 hours after dosing

Common Secondary Causes of Disease Processes Associated With Osteoporosis Endocrine disorders Hyperthyroidism Primary hyperparathyroidism Hypogonadism Cushing syndrome Rheumatologic disorders Rheumatoid arthritis Systemic lupus erythematosus Ankylosing spondylitis Juvenile polyarticular arthritis Malignancy Multiple myeloma Pharmacotherapy Glucocorticoid excess L-thyroxine overreplacement Anticonvulsants (phenytoin or phenobarbital) Lithium, aluminum Cytotoxic drugs, immunosuppressants (cyclosporine A, tacrolimus) Heparin (long-term) Drugs causing hypogonadism (methotrexate, antimetabolite chemotherapy, depo-medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists such as buserelin, depoprovera aromatase inhibitors, leuprolide, and nafarelin) Gastrointestinal disease Chronic liver disease (especially primary biliary cirrhosis and primary sclerosing cholangitis) Inflammatory bowel disease (particularly Crohn disease) Celiac disease Gastric bypass or gastrectomy Renal insufficiency or failure Miscellaneous causes Vitamin D deficiency of any cause Alcohol abuse Anorexia nervosa, malnutrition Movement disorders (Parkinson disease) Amyloidosis Acquired immunodeficiency syndrome, human immunodeficiency virus Chronic obstructive pulmonary disease Cerebrovascular accident Multiple sclerosis Prolonged bed rest or wheelchair bound from any cause Lab Tests To Exclude Secondary Causes CBC Serum creatinine Serum calcium, phosphorous, magnesium Alkaline phosphatase TSH ESR/ CRP 24 hr urine Calcium, Cr Intact PTH 25 Vitamin D UPEP, SPEP Men- Testosterone Women- Estradiol, LH, FSH, Prolactin Tissue transglutaminase antibodies 24 hour urinary free cortisol

Laboratory Tests in Osteoporosis ICSI Guidelines for Laboratory Testing in Patients With Newly Diagnosed Osteoporosis For patients with Z score > 1.0 (patients less likely to have secondary causes of osteoporosis) Serum creatinine  - Renal failure is associated with secondary hyperparathyroidism Liver function tests  - Intrinsic liver diseases and cholestatic disorders are associated with multifactorial causes of increased risk of osteoporosis Serum phosphorus  - Decreased in patients with osteomalacia Serum calcium  - Increased in patients with hyperparathyroidism and decreased in those with malabsorption or vitamin D deficiency 24 hr Urinary calcium excretion  - 24-hour urinary calcium excretion on a high calcium intake diet screens for malabsorption and hypercalciuria—a correctable cause of bone loss; low 24-hour urinary calcium excretion suggests vitamin D deficiency, osteomalacia, or malabsorption due to small bowel disease such as celiac sprue Alkaline phosphatase  - Increased in patients with Paget disease of bone, prolonged immobilization, acute fractures, and other bone diseases Thyroid studies TSH (thyrotropin and thyroxine)  - Hyperthyroidism-associated bone loss Sedimentation rate or C-reactive protein  - May indicate an inflammatory process or monoclonal gammopathy associated with bone loss) Complete blood cell count  - To evaluate for bone marrow malignancy, infiltrative processes (anemia, low WBC, or low platelets), or malabsorption (anemia, microcytosis, or macrocytosis) Serum 25-hydroxy vitamin D or 1,25 dihydroxy vitamin D - To identify vitamin D deficiency Serum intact (whole-molecule) PTH  - Screening for hyperparathyroidism 24 h urine Collagen Cross-Linked N-Telopeptide test For patients with Z score < 1.0 or premature osteoporotic fracture (patients at higher risk of having secondary causes of osteoporosis) All the above tests plus the following additional tests Serum testosterone (total and free)  - Screening for hypogonadism in men; if abnormal, LH, FSH, and prolactin measurements may be indicated to determine the cause of the hypogonadism Serum estradiol  - Screening for hypogonadism in premenopausal or perimenopausal women; if abnormal, LH, FSH, and prolactin measurements may be indicated to determine the cause of the hypogonadism Tissue transglutaminase antibodies  - If gluten enteropathy is suspected clinically 24-hour urinary free cortisol and overnight dexamethasone suppression test  - If hypercortisolemia is suspected Serum and urine protein electrophoresis with immunoelectrophoresis as indicated  - If monoclonal gammopathy is suspected *FSH=follicle-stimulating hormone; LH=luteinizing hormone; PTH=parathyroid hormone; WBC=white blood cell count.   ICSI=Institute for Clinical Systems Improvement

Clinical Assessment of Osteoporosis in Men Clinical History: Medical Problems: Hypogonadism Glucocorticoid excess Alcohol overuse Hyperthyroidism Hyperparathyroidism Multiple myeloma RA, SLE, etc. Celiac disease Nephrolithiasis COPD Cigarette smoking Low dietary calcium intake Medications: Glucocorticoids GnRH agonists AnticonvulsantsChemotherapeutics Immunosuppresnets (eg, Cyclosporin A) Methotrexate Heparin Hypervitaminosis A Lab Assessment: Cr, Ca, phosphorus, alk phos, albumin, LFT, CBC, TSH, Testosterone, 25(OH) D, 24 h urine calcium & creatine. If indicated: Serum protein electrophoresis, Intact PTH, 24 h urine cortisol, Celiac panel (antigliadin/antiendomysial antibodies), Skeletal turnover maker (serum N-telopeptide, serum C-telopeptide, osteocalcin)

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        2011