Issues in Bone Health

Educational Objectives

The goal of this program is to improve diagnosis and treatment of secondary hyperparathyroidism (HPTH) and pre­vention of osteoporosis. After hearing and assimilating this program, the clinician will be better able to:

1.   Counsel patients about adequate calcium and vitamin D intake.

2.   Discuss the relationship between parathyroid hormone (PTH) and bone mineral density (BMD).

3.   Recognize and treat patients at risk for secondary HPTH.

4.   Identify appropriate candidates for BMD testing.

5.   Diagnose and treat patients at risk for fractures due to reduced BMD and/or osteoporosis.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Piziak is on the Speakers’ Bureaus of GlaxoSmithKline, Procter & Gamble, sanofi aventis, Arena, Amgen, Merck, Roche, and No­vartis. Dr. Piziak has received research support from Novartis, Arena, Procter & Gamble and Eli Lilly. Dr. Piziak presented information that is related to off-label or investigational use of a therapy, product, or device. Dr. Christian and the planning committee reported nothing to disclose.

Acknowledgments

Dr. Christian was recorded at Women’s Health Issues: Perception, Prevention, and Practice, sponsored by the University of Vermont College of Medicine, and held May 6-8, 2009, in Burlington, VT. Dr. Piziak was recorded at The Female Patient: Current Issues in the Care of Women, sponsored by Scott & White and Texas A&M Health Science Center, and held June 15-19, 2009, on South Padre Island, TX. The Audio-Digest Foundation thanks the speakers and the sponsors for their coop­eration in the production of this program.

Role of Parathyroid Hormone in Bone Health

Rose C. Christian, MD, Assistant Professor, Department of Medicine, Divsion of Endocrinology, Diabetes, and Metabolism, University of Vermont College of Medicine, Burlington, VT

General considerations: 1 in 2 women affected by osteoporosis; fracture prevention goal of screening and treatment; tools to improve bone health and reduce fracture risk  —  bone mineral density (BMD) screening; exercise; lifestyle changes; improved nutrition; drug therapy

Calcium and vitamin D: little vitamin D present naturally in food other than cod liver oil; National Institutes of Health (NIH) recommended intake  —  1000 mg per day for premenopausal woman; 1500 mg per day for postmeno­pausal or estrogen-deficient woman; 4 to 5 servings of dairy per day or 10 cups of broccoli; average dairy serving 300 mg; average dietary calcium intake for women in United States <600 mg per day; patients often believe cal­cium intake adequate or have excuses for inadequate intake; 300 to 400 mg of calcium lost per day through urine, feces, and sweat; patient in negative calcium balance if not absorbing at least 400 mg of elemental calcium per day; vitamin D  —  enhances calcium absorption when dietary intake low; 400 IU per day prevents rickets in children; 400 IU never shown to prevent fractures or correct secondary hyperparathyroidism (HPTH) in adults; current rec­ommendation 1000 IU per day; new recommendations expected in 2010; causes of hypovitaminosis D  —sunblock (primary cause); dark skin; aging; small bowel disorders; poor renal function; obesity; glucocorticoids; calcium in­take vs absorption  —  calcium carbonate most available supplement, but also least absorbable (requires acid envi­ronment); low gastric acid levels common due to aging, use of proton pump inhibitors (PPIs), H₂ blockers, and gastric surgery; poor calcium absorption also attributed to use of glucocorticoids and to high phytate diet (high veg­etable/fiber diet binds calcium in intestine)

Assessing absorption: 24-hr urine calcium  —  >300 mg indicates calcium wasting; <150 mg indicates poor absorp­tion (with adequate intake); standards available for premenopausal and postmenopausal women; disadvantages  —  inconvenient test; prone to patient error; results affected by medications; high or low urine volume may confound results; alternative tests  —  fecal analysis “great test” but not highly available; measurement of parathyroid hor­mone (PTH)

Parathyroid hormone: body programmed to defend against hypocalcemia at any cost; serum calcium levels main­tained at expense of skeletal stores; >99% of calcium in body resides in skeletal system and available at any time; PTH released in response to low blood calcium levels; nutritional secondary hyperparathyroidism caused by nega­tive calcium balance; PTH acts through receptors in bone and kidney (no receptors in gastrointestinal [GI] tract); serum calcium levels most important regulator of PTH release; vitamin D does not regulate PTH release; actions on kidney  —  increases reabsorption of calcium; stimulates synthesis of 1,25-dihydroxyvitamin D; raises serum cal­cium levels by reducing urinary calcium losses and increasing GI absorption of calcium; action on bone  —  increases number and activity of osteoblasts; osteoblasts then activate osteoclasts; results in release of stored cal­cium from bone surface (immediate effect); over long term, results in accelerated loss of cortical bone, leading to increased risk for fracture

Risk factors for secondary HPTH: surgery  —  any surgery that reduces or eliminates stomach acid (eg, bariatric sur­gery), Whipple procedure; pancreatectomy; small bowel resection; medications  —  glucocorticoids; anticonvul­sants; significant urinary calcium and magnesium loss with loop diuretics; antiretrovirals; PPIs; sunscreen; medical conditions  —  pancreatic insufficiency (eg, cystic fibrosis, celiac sprue); chronic liver disease; chronic diarrhea; small bowel disease; aging; obesity; study looking at vitamin D deficiency in preoperative bariatric surgery patients showed 57% of patients vitamin D deficient; black patients twice as likely to be vitamin D deficient as white pa­tients; 24% of patients with normal renal function had secondary HPTH; pelvic irradiation  —  small bowel irradia­tion may cause recurrent small bowel obstructions due to scarring, chronic enteritis and, ultimately, malabsorption; diet  —  high sodium; high soda; very low fat; high phytate

Reasons to test PTH: high risk for secondary HPTH due to chronic medical condition (eg, Crohn’s disease, celiac sprue); initiation of bisphosphonate (BSP) therapy; osteoporosis treatment failure; hip or pelvic fractures; bariatric surgery “survivor”

Measuring PTH: measure PTH and calcium before initiating BSP therapy; hypocalcemia only contraindication for BSP therapy; secondary HPTH predisposes patient to hypocalcemia after intravenous (IV) BSP therapy; >40% of patients unresponsive to osteoporosis therapy have other conditions that may play role; insufficient calcium and vi­tamin D can reduce effectiveness of BSP therapy; study  —  120 women in late 60s randomized to alendronate (Fosa­max) with or without high-dose vitamin D; women treated with alendronate plus calcium and vitamin D had significantly greater increase in BMD of lumbar spine than women randomized to alendronate alone; data suggest secondary hyperparathyroidism, if not detected and corrected, may reduce effectiveness of oral BSP therapy; test­ing of PTH in all patients with hip or pelvic fractures recommended; data show 52% of patients hospitalized with hip or pelvic fractures have nutritional secondary HPTH (low vitamin D and high PTH); hip fracture patients with secondary HPTH more likely to refracture; bariatric surgery  —measure PTH in all patients postsurgery; skeletal complications manifested clinically by elevated alkaline phosphatase and PTH, and by refractory hypovitaminosis D; treatment  —50,000 IU of vitamin D₂ (not available over-the-counter); maintenance dose typically 1 to 3 times weekly for lifetime; calcium 2 to 3 g per day; treatment issues  —  identify and address all conditions predisposing patient to malabsorption; correct hypovitaminosis D; increase calcium intake; enhance calcium absorption; recom­mend patient take calcium supplement with meals; calcium citrate, chewable calcium or liquid calcium options for patients with low gastric acid; reduce urinary losses by adhering to low sodium diet, calcium-sparing diuretics, and reducing caffeine

Treatment protocol for bariatric surgery and renal transplant patients: PTH >65 pg/mL and vitamin D level <30 mg/mL; increase calcium intake and ergocalciferol (vitamin D₂; should be taken with meals); high-dose vitamin D₂ (50,000 IU 3 times per week) to replete stores; obese patients significantly deficient in vitamin D; maintenance vi­tamin D dosing  —  vitamin D₃ 1000 IU per day with normal GI tract; 2000 to 4000 IU per day if patient has problem with absorption; vitamin D₂ 50,000 IU once or twice weekly for bariatric surgical patient; phototherapy recom­mended if patient unresponsive to supplementation; repeat PTH testing 1 mo after start of maintenance therapy

Additional considerations: not all patients with vitamin D deficiency have secondary HPTH; also, not all patients with secondary HPTH deficient in vitamin D; increasing vitamin D levels without increasing calcium intake will not correct secondary HPTH; secondary HPTH reduces efficacy of BSP therapy; untreated secondary HPTH leads to bone loss and bone pain, and predisposes patient to fractures; patients at high risk should be screened routinely and treated until both parathyroid and vitamin D levels normal

Osteoporosis: Diagnosis and Therapy

Veronica Piziak, MD, PhD, Professor of Endocrinology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX

General considerations: annual incidence (United States) of osteoporotic fractures  —  300,000 hip; 250,000 wrist; 700,000 vertebral; »15% of men in United States have osteoporosis; according to National Institutes of Health (NIGH), focus should be on decreasing incidence of fractures rather than improving BMD; trabecular bone markedly diminished in osteoporosis; medications can restore vertical trabeculations

Screening guidelines: Bone Mass Act (July 1998)  —  estrogen deficiency (in women and men; hypogonadal state in man justifies reimbursement for dual-energy X-ray absorptiometry [DEXA] screening); long-term corticosteroid therapy; radiologic abnormalities suggestive of osteoporosis (eg, loss of height); HPTH; treatment for osteoporosis with approved medication; updated screening guidelines  —  postmenopausal woman <65 yr of age with ³1 risk fac­tors for osteoporosis; women going through menopause with risk factors; woman ³65 yr of age without risk fac­tors; National Osteoporosis Foundation (NOF) standards recommend screening anyone ³50 yr of age; postmenopausal woman who has discontinued hormone therapy; woman >50 yr of age with fracture; long-term use of aromatase inhibitors; patient with hyperthyroidism or HPTH

DEXA scan: measures BMD at any site; hip most reliable site; makes diagnosis of osteoporosis; predicts risk for fracture only in postmenopausal women not taking bone-active agents; allows for monitoring of patient on bone-ac­tive agents (repeat DEXA shows changes in BMD, but does not predict risk for fracture); predicts risk for hip frac­ture regardless of site measured; World Health Organization (WHO) diagnostic categories  —  T score compared to mean T score in young adults; T score 0 to -1 normal, -1 to -2.5 osteopenia, and £-2 osteoporosis; DEXA not diag­nostic for type of metabolic bone disease; WHO definition considers only most common metabolic bone diseases; bone strength not exactly correlated with BMD; mineral-to-matrix ratio important (patient with osteomalacia [poor mineralization] may have T score consistent with osteoporosis); predicting risk for fracture  —  DEXA does not cor­relate with risk for fracture in young people (20-30 yr of age); young patient may be at low risk for fracture with T score of -4.0; DEXA begins to correlate at 50 yr of age; heightened concern unwarranted in young patient with low BMD, but useful as motivational tool for lifestyle changes; assess for metabolic bone disease in young patient with fracture

Monitoring therapy and BMD: no reason for concern if BMD does not increase; data show reduced risk for fracture in patients on alendronate; comparing DEXA scans  —  look for serial changes only; check differences in BMD in g/cm²; compare with least significant change (LSC; found in fine print at bottom of scan images or in report; repre­sents error inherent in scanner); only differences in BMD exceeding LSC may be interpreted as real changes; poor medication compliance most common cause for lack of improvement or loss of BMD; data show »50% of patients fail to take medication adequately; composite data from number of studies show medication confers fracture pro­tection even in patients who did not have increase (or had small loss) in BMD

Who to treat: patients with osteoporosis; postmenopausal women with vertebral or hip fractures; patients >50 yr of age with vertebral or hip fractures; data show low number needed to treat to prevent fracture; World Health Organi­zation fracture risk calculator (FRAX)  —  calculates risk for major osteoporotic fracture over next 10 yr; updated NOF guidelines  —  initiate treatment in postmenopausal women and men ³50 yr of age with hip or vertebral frac­ture, other previous fracture and low bone mass, T score <-2.5, low bone mass and 10-yr hip fracture probability ³3%, or 10-yr major osteoporotic-related fracture probability ³20%

Estrogen: 86% response rate with average dosage (ie, low-dose estrogen used to treat menopausal symptoms); works through transforming growth factor (TGF)-b pathway;  patients at high risk (poor responders)  —  low calcium in­take, smokers, decreased GI transit time, excess thyroid hormone replacement, cystic fibrosis, and history of trans­plantation surgery; raloxifene  —  approved for osteoporosis prevention and therapy; decreases risk for spinal fracture only; increased risk for thrombotic events, particularly in patients >65 yr of age

Bisphosphonates: alendronate  —  generic formulation available; weekly dosing can cause GI irritation; (some gener­ics not well coated); risedronate (Actonel)  —  150 mg monthly dosing; comparable in safety and efficacy to previ­ous dose of 35 mg/wk; administered with 30-min wait before eating; approved for postmenopausal osteoporosis, corticosteroid-induced disease, and for men; some studies show less esophageal irritation; ibandronate (Boniva)  —  150 mg once monthly; administered with 60-min wait before eating; approved for treatment of postmenopausal os­teoporosis and prevention of vertebral fractures; BSPs best agents for prevention of osteoporosis; work fairly rap­idly to decrease fracture risk and work over long term

Intravenous (IV) BSPs: administered in clinic setting; potential for flu-like syndrome (lasting 2 to 3 days), injection site reactions, and renal toxicity (check creatinine before every dose); long-term use of all BSPs associated with os­teonecrosis of jaw; contraindicated with hypocalcemia; obtain calcium level before administering; »0.5% of pa­tients experience severe bone pain; ibandronate  —  3 mg in 15-sec IV push; administered every 3 mo; few side effects; covered by Medicare part B; zolendronic acid  —  approved for postmenopausal osteoporosis; once yearly dosing; 5 mg/100 mL in 15-min infusion; side effects include hypocalcemia, flu-like syndrome, and headache; con­traindicated in pregnancy or with creatinine clearance <35 mL/min (potential for renal damage; check creatinine level before each infusion); ensure patient taking calcium and well hydrated; data show 70% decrease in risk for spinal fracture and 41% decrease in risk for hip fracture (comparable to other BSPs); data show increased risk for atrial fibrillation; approved for men, glucocorticoid-induced disease, and prevention of osteoporosis; Medicare coding  —  2 codes necessary for reimbursement; Medicare requires T score £-2.5 and second code indicating pa­tient cannot take oral BSP; speaker recommends using 995.29 (unspecified adverse effect of other drug)

Other options: strontium  —  not approved by Food and Drug Administration; similar to calcium in absorption; incor­porated into bone and eliminated by kidneys (avoid in patients with renal insufficiency); 2 g/day for 2 yr shown to decrease vertebral fractures; artifactual increase in BMD; teriparatide (Forteo)  —  fragment of PTH; option for pa­tients unable to tolerate IV or oral BSP; indicated for severe osteoporosis; increases BMD, but effect less if used af­ter alendronate; few side effects; data show significant decreases in nonvertebral fractures; contraindicated in Paget’s disease and other metabolic bone diseases; ineffective for osteomalacia; do not use if vitamin D level low or skeletal malignancies present; follow with BSP or other antiresorptive agent; denosumab  —inhibitor of RANK li­gand; binds to precursors of osteoclasts; excess RANK ligand (caused by low estrogen, inflammation) activates os­teoclasts and causes bone destruction; 60-mg subcutaneous dose every 6 mo; approval pending

Suggested Reading

Barone A et al: Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density response to alen­dronate in elderly women with osteoporosis: a randomized controlled trial. J Am Geriatr Soc 55:752, 2007; Breuil V et al: Outcome of osteoporotic pelvic fractures: an underestimated severity. Survey of 60 cases. Joint Bone Spine 75:585, 2008; Gemmel K et al: Vitamin D deficiency in preoperative bariatric surgery patients. Surg Obes Relat Dis 5:54, 2009; Giusti A et al: High prevalence of secondary hyperparathyroidism due to hypovitaminosis D in hospitalized elderly with and without hip fracture. J Endocrinol Invest 29:809, 2006; Iglesias CP et al: The cost utility of bisphosphonate treatment in established osteoporosis. QJM 95:305, 2002; Lewiecki EM: Denosumab update. Curr Opin Rheumatol 21:369, 2009; Kurland ES et al: The importance of bisphosphonate therapy in maintaining bone mass in men after therapy with teriparatide [human para­thyroid hormone (1-34)]. Osteoporos Int 15:992, 2004; Seeman E et al: Strontium ranelate reduces the risk of vertebral fractures in patients with osteopenia. J Bone Miner Res 23:433, 2008; Siris ES et al: Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108, 2004; Reid DM et al: Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomized controlled trial. Lancet 373:1253, 2009.