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 loww 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. 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. Hyperhomocysteinemia--Associated with increased risk of fracture
  15. 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)
  8. Prolonged heparin exposure
  9. Celiac sprue through vit. D malabsorption
  10. Rheumatoid arthritis?
  11. Use of Proton-Pump Inhibitors (click link for details)
  12. Patients with history of Urolithiasis are at increased risk for osteoporosis (click link for details)
  1. Diabetes Mellitus is associated with increased risk of fracture in women with osteoporosis at any given BMD (JAMA 305:2184, 2011-JW)

IV. Diagnosis

  1. Often diagnosed as incidental finding on xray done for other reasons; n.b. 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 < -2.5
  1. 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)
  1. 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)
    1. "FRAX" algorithms assess 10-year risk of major osteoporotic fracture (http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9)
  2. Adequate intake of Calcium during bone-forming years & beyond (per Institute of Medicine and National Academy of Sciences)
CaCO3 500mg = 200mg elemental Ca
CaCitrate 950mg = 200mg elemental Ca
  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
    6. In a study in 36,282 postmenopausal women randomized to CaCO3 1g/d + Vit. D 400IU/d vs. placebo, over 7y f/u, there was no sig. diff. in overall incidence of spine, hip, or total fractures, though among the subgroup of women not using supplemental Ca/Vit. D outside the treatment protocol, RR for hip fx was sig. lower in supplemented group (HR 0.7); The active-treatment group had sig. higher incidence of kidney stones (WHI Trial; NEJM 354:669, 2006--JW)
    7. Potential toxicity of supplemental calcium
      1. May increase mortality in pts with Renal Failure
      2. Ca supplements may accelerate vascular calcification and increase mortality  in older women and in pts with renal failure.
      3. See WHI data above re: association with kidney stones
      4. In a meta-analysis of 5 randomized trials of Ca supplements (500mg/d or more) vs. placebo, involving of 8,000 pts  (77% women; mean age for participants in each study was > 40yo), over median 3.6y f/u, incidence of MI was sig. greater in Ca recipients (HR 1.31); no sig. diff. in incidence of CVA or death.  The authors estimate an absolute risk increase of 14 MIs for a population of 1,000 people treated with Ca supplements for 5y.  (BMJ 341:c3691, 2010-JW)
      5. The WHI randomized about 36,000 women who did not report baseline Ca use to (Ca 1g + vit D 400IU) vs. placebo.  In an analysis of data from the WHI which excluded pts who did not report baseline use of Ca, those randomized to Ca/Vit D had sig. increase in incidence of MI c/w placebo (HR 1.2); among women who used Ca at baseline, there was no sig. diff. in MI between those randomized to Ca/Vit D. vs. placebo.  In the same publication, in a meta-analysis of three randomized trials with 20,000 participants and mean duration about 6y, randomization to Ca/vit D was associated with sig. increases in incidence of MI (RR 1.2) and CVA (RR 1.2) (BMJ 342:d2040, 2011-JW)
  1. Consider Vitamin D combined with Calcium if at risk for deficiency (home-bound, poor nutritional status, unsunny climate)--Click link for details
  2. Hormone Replacement Therapy (see also below)
  3. Folic Acid
    1. Hyperhomocysteinemia is ass'd with increased risk of osteoporotic fractures in the elderly
    2. In a study in 628 pts > 65yo s/p ischemic CVA > 1y previously and with residual hemiplegia randomized to (folate 5mg + mecobalamin 1.5mg PO QD) vs. placebo, over 2y f/u, incidence of hip fx was sig. lower in folate group (1 fx per 100 pt-years vs. 4.3 w/placebo) (JAMA 293:1082, 2005--abst)
  4. 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)
  5. 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)
  6. Beta-Blockers
    1. May reduce risk of osteoporosis by inhibiting bone resorption
    2. Current beta-blocker use ass'd with OR 0.83 for fracture in one case-control study (JAMA 292:1326, 2004--JW)
  7. Organic Nitrates
    1. In a study in 243 menopausal women without osteoporosis randomized to NTG ointment vs. placebo x 24mos, at 2y, NTG group had sig. greater increases in lumbad spine BMD and total hip BMD; no sig. diff.in incidence of serious adverse effects, though a sig. greater percentage of the NTG group d/c'd the study treatment in first year b/c of headache.  (JAMA 305:800, 2011-JW)
  8. "Weight-bearing" exercise, in bone-forming years and beyond

VI. Screening for Osteoporosis-click link for details

VII. Treatment of Osteoporosis and Ostopenia

North American Menopause Society 2010 recommends tx for T-score < -2.5, h/o osteoporotic hip or vertebral fx, or T-score from (-1.0 to -2.5) plus FRAX-calculated 10y risk of hip fx ≥ 3% or any major fx ≥ 20%

  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. Reduces fractures c/w placebo
  2. May also provide some analgesia in pts after fracture
  3. Less effective at increasing bone density in women than estrogen 
  4. Adverse effects
    1. Parenteral form causes flushing, skin rash, nausea, dizziness
    2. Intranasal form only causes nasal irritation
  5. Lack of response in some patients has been attributed to "low-turnover" state or perhaps b/c of antibody formation
  1. Bisphosphonates
  1. Inhibit bone resorption
  2. All persist unmetabolized in bone for months-years
  3. Avoid in patients with renal impairment
  4. Potential adverse effects
    1. May be associated with elevation in risk for esophageal Ca in case-control studies, though findings are inconsistent (JAMA 304:657, 2010-JW; BMJ 341:c4444, 2010-JW)
    2. GI side effects e.g. esophagitis
    3. Aseptic necrosis of the jaw
    4. Acute tubular necrosis
    5. Possibly, atypical femur fractures
  5. 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. Alendronate for treatment of osteoporosis in men
    1. 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. Duration of treatment with Alendronate
    1. In a study in 1,099 postmenopausal women on alendronate 5-10mg/d for at least 5y randomized to continued treatment vs. placebo; all took Ca/Vit. D supplementation.  After 5y, there was no sig. diff. between the groups in the incidence of nonvertebral fx though alendronate group had sig. fewer symptomatic vertebral fx (2.4% vs. 5.3%) ("Fracture Intervention Trial Long-term Extention" ("FLEX"), JAMA 296:2927, 2006--JW)
  6. Alendronate for osteopenia
    1. In analsys of data from the Fracture Intervention Trial re: 3,737 postmenopausal women 55-80yo with femoral neck T-scores -1.6 to -2.5 randomized to alendronate vs. placebo x 4.5y, alendronate group had sig. reductions in both clinically recognized vertebral fx (RR 0.4) and radiologically identifiable vertebral fx (RR 0.59), though reductions were not sig. among subgroup of pts with no vertebral fx at baseline (Mayo Clin. Proc. 80:343, 2005--JW)
  7. 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)
  8. No need for cyclic dosing
  9. 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, Reclast) given IV Q3mos
    1. Increased BMD c/w placebo in one randomized trial (NEJM 346:653, 2002--JW)
  5. Ibandronate (Boniva) 2.5mg QD or 150mg Qmo (I have not seen any studies examining this drug's efficacy in reducing fracture incidence--ER)
  1. Denosumab (Prolia)
    1. A humanized monoclonal antibody to receptor activator of nuclear factor-B ligand (RANKL), a cytokine, expressed by osteoblasts; binding RANKL reduces osteoclastic activity
    2. In a study in 7,868 women with postmenopausal osteoporosis randomized to denosumab 60mg SQ vs. placebo Q6mos x 3y, denosumab pts had sig. lower incidence of new vertebral fx (RR 0.32) and hip fx (RR 0.6); no sig. diff. in adverse events (NEJM 361:818, 2009-JW)
    3. Can exacerbate pre-existing hypocalcemia; also associated with dermatitis
  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. Use as of 2012 is recommended not to exceed 2 years--See below re: what to do after that time
    3. Shown to increase BMD in men as well as women
    4. Can be used in patients in whom bisphosphonate therapy is ineffective
    5. Evidence of efficacy
      1. 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)
      2. In a study in 2,679 postmenopausal women with osteoporosis (81% of whom had no prior vertebral fracture) randomized to 100ug parathyroid hormone SQ vs. placebo QD x 18mos, PTH group had sig. greater increases in lumbar spine and hip BMD but decreased at the distal radius c/w placebo; PTH group had sig. lower incidence of new or worsened vertebral fx (1.4% vs. 3.4%). PTH recipients had sig. higher incidence of hypercalcemia and nausea (Ann. Int. Med. 146:326, 2007--JW)
    6. Use as an adjunct to Alendronate
      1. In a study in 126 women with osteoporosis all on alendronate x at least 1y randomized to daily SQ PTH x 15mos, daily SQ PTH on/off for 3-month cycles x 15mos, or no PTH; all continued alendronate during the study; at 15mos, both PTH groups had sig. greater increases in spine BMD than the alendronate-only group but there was no sig. diff. between the two PTh regimens (NEJM 353:566, 2005--abst)
    7. Adverse effects
      1. Hypercalcemia, nausea, and headache; also orthostatic hypotension with the first few doses
      2. 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)
      1. In a follow-up report from this study, the 119 pts who had received parathyroid hormone were randomized to alendronate 10mg/d vs. placebo x 1y; at end of one year alendronate recipients had sig. lower reductions in BMD (NEJM 353:555, 2005--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)
    5. In a study in 372 postmenopausal women 50-75yo with osteoporosis randomized to:
      • Conjugated estrogen 0.625mg + medroxyprogesterone 2.5mg PO QD
      • Etidronate 200mg PO QD (cycle on/off 14d/10d)
      • Eel calcitonin 20IU Qwk
      • Vitamin D 1mcg active QD
      • Vitamin K 45mg QD
      • Placebo

      2y incidence of the vertebral fracture was sig. reduced (c/w placebo) for the following treatments: estrogen/medroxyprogesterone (RR 0.35), etidronate (RR 0.40), calcitonin (RR 0.41), and vitamin K (RR 0.44) (Am. J. Med. 117:549, 2004--AFP)

  2. Treatment with Potassium Citrate
    1. In a study in 161 postmenopausal women with low bone mass randomized to potassium citrate 30mEq/d vs. a KCl control x 12mos (all also received Ca/Vit. D); at 12mos, the potassium citrate group had sig. greater increase in lumbar spine BMD (J. Am. Soc. Nephrol. 17:3213, 2006--JW)
  3. Treatment response should be assessed with serial bone densitometry
  4. Fall prevention: rubber-soled shoes, walkers, proper lifting technique, avoid sedating/unbalancing meds; periodic checking of visual acuity; home modifications
  5. In male patients with osteoporotis, check serum total/free testosterone; if low, replacement may be necessary
  6. Treatment of Hyperhomocysteinemia
    1. In a study in 628 pts > 65yo with CVA, hyperhomocysteinemia and low vitamin B12 levels, but no previous osteoporotic fx, randomized to (folate 5mg + mecobalamine 1.5mg) QD vs. placebo, over 2y f/u, active tx group had sig. lower incidence of fx (RR 0.78, absolute risk reduction 6.7%) despite no sig. diff. in change of hip BMD (JAMA 293:1082, 2005--JW)
  7. See section on Corticosteroids for info on osteoporosis prevention in pts on chronic corticosteroids
  8. Treatment of osteoporotic vertebral fractures
    1. In most cases, can manage with decreased activity for 1-2wks then bracing
    2. Calcitonin (either intranasal or subcutaneous) can provide pain relief, often within days
    3. Vertebroplasty (percutaneous injection of a cement-like substance into the affected vertebral body)-An option if pain not improved within 2wks
      1. In a study in 131 pts with painful osteoporotic vertebral fractures randomized to vertebroplasty vs. a sham procedure, in intent-to-treat analysis, there was no sig. diff. in pain and disability scores at 3d, 2wks, and 1mo post-procedure. (NEJM 361:569, 2009-JW)
      2. In a study in 202 pts with painful vertebral fractures of < 6wks symptom duration randomized to vertebroplasty vs. conservative management, there was sig. greater lowering of mean pain scores at 1y in the vertebroplasty group (Lancet 8/10/2010 e-pub ahead of printing; http://dx.doi.org/10.1016/S0140-6736(10)60954-3)
    4. Kyphoplasty (inflation of a balloon in the affected vertebral body to restore vertebral height, then injection of cement)
      1. In a study in 78 pts with osteoporotic vertebral fractures of < 1y duration randomized to vertebroplasty vs. a sham procedure, there were no sig. diffs in symptoms at 1wk, 1mo, 3mos, or 6mos. (NEJM 361:557, 2009-JW)
      2. In a study in 300 pts with acute vertebral compression fx randomized to kyphoplasty vs. supportive care alone, at 1mo, kyphoplasty pts had sig. greater improvements in quality of life, back pain, and function ("FREE" trial; Lancet 373:1016, 2009-JW)