OSTEOPOROSIS

I. Normal bone physiology

  1. Ongoing resorption by osteoclasts and laying down of new matrix by osteoblasts
  2. Essentially the same process in cortical & trabecular bone, but rate of turnover is higher in trabecular bone; therefore, that's where you see osteoporotic changes first (spine, pelvis, distal radius, proximal femur)
  3. Peak bone mass usually achieved by age 30-35, followed by gradual decline
  1. Postmenopausal women lose 3-4% of bone mass/yr
  2. Rate of bone low is equal in men & women after age 65
  3. 90% of women & 50% of men have osteoporosis by 80yo

II. Pathophysiology

  1. Type I: "Postmenopausal."
  1. Loss of bone cancellous > cortical, so get vert. compr. fx.
  2. Problem is mostly excessive osteoclastic activity
  1. Type II: "Age-related"
  1. Affects both men and women.
  2. Loss of bone cancellous = cortical, so get hip and vert. fx.
  3. Problem is mostly inadequate osteoblastic activity
  1. Also: "Low-turnover" vs. "high-turnover" state: differentiated with "bone turnover markers"

III. Epidemiology

    Risk Factors:

  1. Age (esp. postmenopausal state in women)
  2. Female gender (lower peak bone mass & faster loss after menopause)
  3. White or Asian ancestry
  4. Poss. familial component
  5. Thin body habitus
  6. Very sedentary lifestyle (weight bearing exercise is preventive)
  7. Heavy alcohol use
  8. Tobacco use
  9. Very low dietary Ca intake (inc. from anorexia; Ann. Int. Med. 133:790, 2000--JW)
  10. High intake of carbonate beverages (ass'd with higher risk of prior fracture in a retrospective cohort study of 460 high school girls--Arch. Ped. Adol. Med. 154:610, 2000--JW)
  11. Family Hx
  12. Low peak bone mass in life. e.g. Ca deficiency in pubertal years
  13. Prolonged estrogen deficiency & amenorrhea, e.g. anovulation
  14. Secondary causes:
  1. Corticoid excess (endogenous or exogenous; perhaps even inhaled!--Chest 106:1722, 1994)
  2. Hyperthyroidism, including iatrogenic (exogenous)
  3. Chronic renal disease, esp RTA
  4. Liver disease
  5. Hyperparathyroidism
  6. Multiple myeloma, leukemia, lymphoma
  7. Dilantin (reduces intestinal Ca absorption), CCS, GnRH, loop diuretics, MTX, Depo, heparin, cyclosporin
  8. Prolonged heparin exposure
  9. Celiac sprue through vit. D malabsorption
  10. Rheumatoid arthritis?, spinal cord injury, depression, severe COPD, CF, BM dz, anorexia, CTD/skeletal Dz (Marfan's, rickets, OI)
  11. Vit D deficiency-several studies show sig number in-pt's [56% in 1 study] Vit d def.  Rec levels >30ng/cc.  elev PTH not 100% sensitive for lo vit d.

IV. Diagnosis

        DDX:  Trauma, neoplasm, osteomalacia, Paget's Dz, infedtion, fibrous dysplasia, March Fx (repetetive stress)

           

  1. Often diagnosed as incidental finding on xray done for other reasons; changes on plain films only visible after 40-50% bone loss!
  1. If suspect, e.g. b/c has had spontaneous fracture:
  1. Risk factors and secondary causes of bone loss (see above)
  2. Fracture history
  3. XRay for path. fx
  4. Px: look for spinal kyphosis, pain, immobility
  1. Bone densitometry-an accurate way to predict fracture risk
  1. Quantitative CT---can check cortical or trabecular bone; high radiation dose, often imprecise
  2. Dual photon abs.-can check all bones; slow and expensive
  3. Dual energy xray absorptiometry ("DEXA")-better reproducibility than DPA, but expensive; usually check lumbar vertebrae or prox. femur
    1. Usually report both a "z-score" (# of SD's from mean of age/sex-matched population) and "t-score" (# of SD's from mean in healthy young gender-matched adults).
    2. WHO defines "Osteopenia" as t-score of -1 to -2.5 and "osteoporosis" as t-score < -2 sd
    3. INTERPRETATION: HIP: Ignore Ward's triangle.  ck cut off line in std place.  if doing f/u scan look to see that images look similar (ie. no rotation, ck lesser troch).  ck that troch/neck/intertroch within 1/2 sd, if not consider tech error.  Lumbar:  R/O scoliosis, deg OA, jewelery, comp fx, aortic ca, paget's, surg chgs. L1-4 most import.  If comparison, >6%diff sig.  No cut off for males.

D.  Laboratory Evaluation:  uncomplicated pt w/ osteoporosis: CMP, CBC, Phos, TSH, 24h urine Ca, males  testosterone.  helps r/o secondary causes (renal insuff, hepatic failure, hyperthroidism, anemia, acidosis, hypercalciuria.  SPEP should be considered in pt's w/ new FX (do SPEP and UPEP).  Consider urine cortisol studies in pts w/ suggestive features.  If serum Ca abnormal (remember to check alb correction, or ionized Ca if needed) or if "severe" bone dz, check PTH and 25OH VitD.  (primary hyperparathyroidism freq assoc w/ inc Ca, secondary inc PTH can occur w/ normal Ca, bbut ususally detected via low 24h urine Ca or dec CrCl.  mild vit D def can occur w/o low Ca, but routine vit D suppl should adeq Tx.

        -664 postmenopausal women w/o known hx dz, meds known to affect bone underwent; CBC, TSH, CMP, 24h urine Ca, 25OH Vit D, PTH.  173 women met inclusion criteria, 55 (32%) found to have previously undx d/o of bone/mineral metabolism.  Authors note Ca, TSH (if on thyroid replacement), 24h urine Ca would have dx 85%, @ est cost of $75/pt screened.  J Clin Endocrinol Metab.  2002 Oct; 87(10):4431-7.

         E.  Broadband ultrasound attenuation

  1. In one prospective study comparing u/s of calcaneus with DEXA of calcaneus and hip in 5,000 women over 65yo followed for avg. of 2y, predicted fractures (hip & elsewhere) to a similar degree as DEXA (Arch. Int. Med 157:629, 1997-JW)

            F.        Bone turnover markers

  1. Provide a way to assess bone metabolism, e.g. during osteoporosis tx, without having to wait months to years to see effects of tx as with DEXA
  2. Markers of bone formation (* = available at UW as of 4/00)
    1. Bone-specific serum Alkaline Phosphatase--10-20% circadian variation*
    2. Osteocalcin (aka "Bone gla-protein")--Possible vit. K-dependent; not well standardized as of 2000; 10-30% circadian variation
    3. Type I procollagen peptides--Not highly specific
  3. Markers of bone resorption
    1. "NTx" (N-telopeptides of helix cross-links)--Done on urine; up to 40% circadian variation so recc'd be done on 24 urine collection*
    2. "PyrlinksD" (Urine deoxypyridinoline)--Ditto
    1. AF, OH-Proline, fasting urine Ca

V. Prevention:

  1. Risk factor modification (see above)
  2. Adequate calcium intake during bone-forming years & beyond (per Institute of Medicine and National Academy of Sciences)
  1. 800mg/d 4-8yo
  2. 1300mg/d 9-18yo
  3. 1000mg/d 19-50yo
  4. 1200mg/d > 50yo
  5. Dietary sources
    1. Usually sufficient but supplements may be required for those who won't/can't take dairy
    2. About 300 mg of Ca in 8oz yogurt, 1cup milk, 1.5oz cheddar cheeze, 2oz American cheese, 5oz canned salmon, 3/4 cup tofu, 10 figs, 6 sardines, or 1cup collared greens. Calcium in wheat bran or spinach is poorly absorbed
  6. Supplemental Calcium
    1. CaCO3 has good bioavailability; cheap; absorption best if taken with meals; take at night to coordinate with diurnal rhythms of bone mineralization; contraindicated in hypercalemia, sarcoid, nephrolithiasis (CaCitrate 950mg QD better in latter case)
    2. CaCO3 500mg = 200mg elemental Ca
    3. CaCitrate 950mg = 200mg elemental Ca (slightly more bioavailable than CaCO3)
    4. Overall bioavailability falls with doses > 500mg of CaCO3.
    5. Very high doses of CaCO3 can lead to the "milk-alkali" syndrome, nephrocalcinosis, and renal insufficiency
  1. Vitamin D & Calcium if at risk for deficiency (home-bound, poor nutritional status, unsunny climate)
  2. Hormone Replacement Therapy (see also below)
  3. Bisphosophonates for prevention of osteoporosis
    1. 1609 postmenopausal women (90% had no osteoporosis) randomized to alendronate 2.5mg/d, alendronate 5mg/d, combined HRT, or placebo, all x 4y. At 2y, half of alendronate group switched to placebo. HRT group had greater increases in BMD; the alendronate-then-placebo group, at 4y, had more increase in BMD than placebo group but less than 4y-of-alendronate-group (Ann. Int. Med. 131:935, 2000--JW)
  4. Thiazide Diuretics
    1. Reduce renal calcium excretion
    2. Ass'd with increased hip (but not vertebral or total body) bone mineral density c/w placebo (Ann. Int. Med. 133:516, 2000--JW)
    3. In a prospective cohort study of 7891 pts > 55yo, current use of thiazide diuretics for > 365d was ass'd with sig. lower risk of hip fracture (RR 0.46); no dose-response relationship observed.  Use > 4 months previously was not associated with any risk reduction (Ann. Int. Med. 139:476, 2003--abst)
  5. "Weight-bearing" exercise, in bone-forming years and beyond

VI. Treatment--NOF as of 7/97 recc's tx for any postmenopausal women w/osteoporosis who has had a vertebral or hip fx, all women w/o h/o fx and T score below -1.5 if risk factors for osteoporotic fx are present (personal h/o fx as an adult, h/o fx in 1st-degree relative, caucasian, "advanced age," female, dementia, poor health/frailty, current smoker, body weight < 127lb, menopause x > 1y, low Ca intake, alcoholism, impaired eyesight despite adequate correction, recurrent falls, or inadequate physical activity), and all women w/o h/o fx and T score below -2.0.

  1. Antiresorptive drugs-used for bone density decreased but above "fx threshold." May need to be accompanied by supplements of Ca & vit. D if dietary intake is inadequate
  1. Estrogen--see also "Hormone Replacement Therapy"
  1. Probably works by reducing osteoclastic activity
  2. Is most effective in early postmenopausal period, e.g. <65yo, but works afterward as well
  3. Protective effects are lost soon after stopping drug so tx probably should be chronic
  4. See below for some studies on combining estrogen + bisphosphonates
  1. Calcitonin (100IU SC/IM QOD or 200IU intranasal QD)
  1. Less effective at increasing bone density than estrogen but does reduce fractures c/w placebo
  2. Parenteral form causes flushing, skin rash, nausea, dizziness; intranasal only causes nasal irritation
  3. Injected form may cause nausea and flushing
  4. Some don't respond, poss. b/c they have "low-turnover" state or perhaps b/c of antibody formation
  5. May also provide some analgesia in pts s/p fractures
  1. Bisphosphonates
  1. Inhibit bone resorption
  2. All persist unmetabolized in bone for months-years
  3. Etidronate (Didronel) 400mg QD
  1. Inhibits bone mineralization, so can cause osteomalacia; therefore, must be given cyclically (2wks/3mos)
  2. Trials through late '95 show safety & efficacy through 7y of use
  3. Etidronate + HRT better than either alone: 72 pts randomized to HRT (Premarin 0.625/d + norgestrel 150mg/d 12d/mo), etidronate (400mg/d x 14d every 12wks), both, or placebo; all were encouraged to exercise and tx'd with Ca (1g/d) and vit. 4 (400IU/d). Placebo group showed sl. decrease in spine & hip BMD at 2y and 4y; no change in etidronate or HRT groups; combined group showed sig. increases at both 2y and 4y; incidence of new vertebral fx (assessed by plain films) sig. less in combined group than w/placebo; hip BMD was sig. increased c/w placebo or either single-tx group (Am. J. Med. 104:219, 1998--AFP)
  1. Alendronate (Fosamax) 10-40mg/d (or 70mg Qwk)
  1. In a randomized trial in 994 postmenopausal women w/osteoporosis, 10mg QD before breakfast reduces risk of spine & hip fx compared with placebo (NEJM 333: 1437, 1495; 1995); in an extended (to 7y) f/u study in the same cohort, continued increases in BMD were seen and no serious side effects detected in women on Alendronate (J. Clin. Endoc. Metab. 85:3109, 2000--JW)
  2. The "Fracture Intervention Trial" (JAMA 280:2077, 1998)
    1. 8705 women 54-81yo with femoral neck BMD < 0.69g/cm2 (corresponds to > 1.5SD below young adult mean) but no vertebral fx randomized to alendronate (5mg/d x 2y then 10mg/d--increased after other studies suggested 10mg/d to be more effective) vs. placebo. All pts with dietary Ca intake < 1g/d received 500mg Ca & 250IU cholecalciferol as well. Over average 4.2y f/u, alendronate group had sig. higher BMD at all sites studies, nonsig. reduction in clinical fx incidence (RR 0.86--though in subgroup of women with baseline femoral neck BMD > 2.5SD below young adult mean, reduction in clinical fx was sig., RR 0.64), and sig. fewer radiographically-assessed vertebral fx (RR 0.56)
  3. 10mg QD ass'd with increased bone density at lumbar spine (sig.) and greater trochanter (nonsig.) in 428 osteoporotic women on postmenopausal HRT (J. Clin. Endocrin. Metab. 84:3076, 1999--JW)
  4. In men: 241 men w/osteoporosis (mean age 63) randomized to alendronate 10mg/d vs. placebo; at avg. 2y f/u mean lumbar spine & femoral neck BMD was sig. more increased in the alendronate group; also, sig. fewer new vertebral fx in alendronate group (7.1% vs. 0.8%) (NEJM 343:604, 2000--JW)
  5. Alendronate + HRT better than either alone
    1. 425 postmenopausal women with low BMD, mean age 61, all s/p hysterectomy and not on HRT at onset rnadomized to alendronate 10mg/d, Premarin 0.625mg/d, both, or double placebo. Over 2y f/u, combined therapy ass'd with sig. greater increase in BMD than either alone; low incidence of fx in the trial so no sig. diff. observed in fx incidence among the groups (J. Clin. Endocr. Metab. 85:720, 2000--JW)
    2. 373 women with osteoporosis 65-90yo randomized to alendronate, hormone therapy, both, or double-placebo; over 3y, combination therapy was ass'd with sig. greater increases in spine and hip BMD than placebo or either tx alone. (JAMA 289:2525, 2003--JW)
  6. No need for cyclic dosing
  7. Side f/x:
    1. Esophagitis
      1. May be severe
      2. Risk is reduced if take in am before any food, drink, or meds, with lots of H2O, and remain upright for 30min after dosing or until first food of day, whichever happens later
      3. 70mg Qwk dose was not ass'd with any difference in upper endoscopic findings (Am. J. Gastroent. 97:58, 2002--JW) or in GI symptoms (Mayo Clin. Proc. 77:1031, 2002--JW) in two randomized trials
    2. Gastric ulcer (see under Risedronate below)
  1. Risedronate (Actonel) 5mg PO QD or 35mg PO Qwk
    1. May cause mild diarrhea, nausea, and abdominal pain
    2. Causes arthralgias in 30%
    3. Causes flu-like syndrome in 10%
    4. Risedronate 5mg/d ass'd with sig. fewer gastric ulcers on EGD at 2wks than Alendronate 10mg/d in a randomized study inb 515 healthy postmenopausal women (4% vs. 13%) (Gastroent. 119:631, 2000--JW)
    5. 5445 women 70-79yo with osteoporosis and 3886 women > 80yo with non-skeletal risk factors for hip fx (poor tandem gait, difficulty in standing from a sitting position, recent falls, etc) randomized to Risedronate vs. placebo; all received Ca supplements.  At 3y f/u, th osteoporosis group had sig. lower hip fx incidence with risedronate (1.9% vs. 3.2% w/placebo); in the "non-skeletal risk factor" group, there was a nonsignificant decrease in hip fx incidence (p = 0.35) (NEJM 344:333, 2001--JW)
    6. Risedronate + HRT better than either alone: 524 postmenopausal women randomized to HRT vs. HRT + risedronate 5mg/d; at 12mos; bone density increase was sig. greater in combination group than HRT group at femoral neck & radius but not L-spine or femoral trochanter.  Fx rate was low and not sig. diff. in the tx groups (J. Clin. Endocrinol. Metab. 86:1890, 2001--JW)
  1. Pamidronate (Aredia) 30mg/d IV
    1. May cause a flu-like syndrome
  2. Tiludronate (Skelid) 400mg/d PO
  3. Clodronate--undergoing clinical trials as of 1998
  4. Zoledronate (Zometa) given IV Q3mos--Increased BMD c/w placebo in one randomized trial (NEJM 346:653, 2002--JW)
  1. Formation-stimulating drugs for bone density below "fx threshold"--all agents are experimental
  1. Fluoride
  1. Originally used after fx in osteoporotic pts
  2. Controlled trials showed it actually increases rates of fx, prob. b.c stimulates formation of cancellous bone at expense of cortical bone
  3. Slow-release formulations at lower doses may hold promise
    1. 200 postmenopausal women with moderately low BMD randomized to 152mg of Na-monofluorophosphate + Ca 1g vs. Ca alone with each meal; at 4y f/u MFP group had sig. higher spine BMD but no diff. in hip BMD; also sig. lower incidence of new vertebral fx (2% vs. 10%) in MFP group (Ann. Int. Med. 129:1, 1998--JW)
  1. Teriparatide (recombinant parathyroid hormone, "Forteo") 20ug SQ QD
    1. Continuous PTH administration leads to bone resorption but intermittent administration stimulates bone formation
    2. 1637 postmenopausal women with h/o atraumatic vertebral fx randomized to PTH 20ug or 40ug SQ QD vs. placebo for mean 18mos. New vertebral fx sig. less common in both PTH groups than placebo (4%, 5%, 14% in 40ug, 20ug, and placebo groups, respectively); ditto for new nonvertebral fx (6%, 6%, and 10%); side f/x sig. more common in tx than placebo group included hypercalcemia, nausea, and headache; also orthostatic hypotension with the first few doses (NEJM 344:1434, 2001--JW)
    3. Shown to increase BMD in men
    4. Associated with increased risk of osteogenic sarcoma when given to rats at high doses (Med. Lett. 45:9, 2003); avoid in patients at increased risk for osteosarcoma, e.g. Paget's disease or unexplained elevations in serum alkaline phosphatase.
  1. HMG CoA-Reductase inhibitors ("statins")
    1. Originally developed for tx of Dyslipidemias
    2. Several studies have shown evidence for bone density increase & decrease of fracture risk
      1. In a case-control study of 3940 pts with fx and about 88,000 controls, RR of fx was 0.55 for pts on a "statin" drug, after adjustment for confounders (JAMA 283:3205, 2000--JW)
      2. In another case-control study of 1,222 pts > 65yo with hip fx and 4,888 controls, OR of fx was 0.5 for pts who used statins in previous 6mos and 0.57 in those who had used in previous 3y; no such association w/other lipid-lowering drugs (JAMA 283:3211, 2000--JW)
      3. In a case-control study of 928 women > 60yo with fx and 2747 age-matched controls, pts who had had statins dispensed > 12x had OR 0.48 for fx than others (Lancet 355:2185, 2000--JW)
      4. In a study of 41 postmenopausal women on statins for hypercholesterolemia c/w 100 age-matched controls not on statins had sig. higher spine & hip bone density (Lancet 355:2218, 2000--JW)
    3. But others haven't...
      1. In a case-control study of 81,880 pts > 50yo with fx and 81,880 age-, sex, and practice-matched controls, OR for fx in current users of statins c/w nonusers was 1.01 (adjusted for smoking, meds & illnesses ass'd with fx risk, and BMI when known) (JAMA 285:1850, 2001--Abst)
      2. In a prospective observational study of 7,846 statin users and 85,870 nonusers (all women 50-79yo) followed for median 3y, after adjusting for potential confounders, there was no sig. diff. in risk for hip, lower arm or wrist, or other fractures, or bone density (Ann. Int. Med. 139:97, 2003)
  1. Comparisons between treatments
    1. In a 12-mo trial of 238 postmenopausal women with (T-score < -2.5 at hip or spine OR (T-score < -2.0 at hip or spine and an additional osteoporosis risk factor)) randomized to parathyroid hormone 100ug/d, alendronate 10mg/d, or both, there were no sig. differences between any of the groups in the increases in lumbar spine or femoral neck BMD measured on DEXA; for total hip and distal radius BMD, however, combination-therapy group had sig. greater increases than parathyroid-hormone-only group, but not sig. greater than alendronate-only group (NEJM 349:1207, 2003--abst)
    2. In a 30-month trial of 83 men 46-85yo with low BMD randomized to alendronate 10mg/d, parathyroid hormone 40ug/d, or both (alendronate therapy starting 6mos before parathyroid hormone therapy), increase in spine and femoral neck BMD was sig. greater in parathyroid hormone-only group c/w other groups (NEJM 349:1216, 2003--abst)
    3. In 299 osteoporotic women randomized to alendronate 10mg QD vs. calcitonin 200IU Intrasal QD, BDM increase at 12mos was sig. greater in alendronate group (L-spine, femoral neck, and greater trochanter) (J. Clin. Endo. Metab. 85:1783, 2000--JW)
    4. Teriparatide 40ug SQ QD associated with significantly greater BMD increase and significantly lower non-vertebral fx incidence c/w alendronate 10mg PO QD in a 14mo randomized trial in 146 postmenopausal osteoporotic women (J. Bone Min. Res. 18:9, 2003--cited in Med. Lett. 45:9, 2003)
  2. Treatment response should be assessed with serial bone densitometry
  3. Fall prevention: rubber-soled shoes, walkers, proper lifting technique, avoid sedating/unbalancing meds; periodic checking of visual acuity; home modifications
  4. In osteoporotic male, check serum total/free testosterone; if low, replacement may be necessary
  5. See section on Corticosteroids for info on osteoporosis prevention in pts on chronic corticosteroids
  6. Vertebroplasty-consider in pt's w/ severe acute, chronic pain secondary to vertebral hemangiomas, comp fx, MM, metastatic CA.  contraindicated w/ coag d/o, infxn near inj site, spinal cord compression, severe vert body collapse.  long term sequelae unknown JFP V55, N7 july 2006

(Sources: AFP monograph 1/96 and other sources as cited)