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A. Overview of Treatmentnavigator

  1. Treatment Recommendations [1,15]
    1. Bone mineral density (BMD) usually via DEXA scans should be determined at baseline [21]
    2. Post-menopausal women with low serum levels of vitamin D should take supplements
    3. All elderly men should ensure adequate calcium + vitamin D intake
    4. Role of calcium and vitamin D supplements for adults with good nutritional intake unclear
    5. Alendronate, risedronate, ibandronate or raloxifene prevent fractures in post-menopausal women with osteoporosis and differences between agents are small [15]
    6. Alendronate, risedronate, raloxifene or parathyroid hormone (PTH) prevent vertebral and non-vertebral fractures [15]
    7. After 5 years on bisphosphonates, reasonable to take a "drug holiday" for up to 5 years, although continued drug reduces new vertebral fractures [3]
    8. Overall, PTH (subcutaneous) likely the most effective agent, followed by bisphosphonates
    9. Adding bisphosphonates to PTH reduces the efficacy of PTH
    10. Calcitonin is marginally effective and is third line therapy, not as effective as others [15]
    11. Hormone replacement therapies (HRT) are no longer recommended for chronic therapy
  2. Calcium + Vitamin D (Vit D)
    1. Previous guidelines recommended all persons at risk for osteoporosis should take supplemental calcium (1000mg/day) + Vit D (400-800IU/day)
    2. At least two randomized studies have now shown no significant reduction in fractures in postmenopausal women taking calcium + Vit D versus placebo [11,12]
    3. Many elderly persons are deficient in vitamin D, particularly in nursing homes
    4. Vit D supplements recommended in elderly persons with low serum levels
    5. Efficacy of calcium + Vit D is not clear at this time and may increase renal stones
    6. Calcium citrate is acceptable in most persons with history of renal stones
  3. Bisphosphonate Therapy
    1. Generally first line for osteopenia and osteoporosis
    2. For patients with demonstrated osteoporosis by BMD or similar test
    3. These agents are extremely potent and generally well tolerated (over 3-5 years)
    4. Discontinuation of alendronate associated with stable BMD (compared with ERT) [5]
    5. Up to 5 years of therapy recommended, then discontinuation is suggested [3,71]
  4. Selective estrogen receptor modifiers (SERMs) [6,7]
    1. SERMs recomended over any hormone replacement therapy (HRT or ERT)
    2. Raloxifene (Evista®) is very effective and is currently only approved SERM
    3. ERT/HRT not routinely recommended in menopausal women due to overall side effects
  5. PTH
    1. Most potent of all agents
    2. Only approved agent that directly stimulates osteoblasts
    3. Only available as subcutaneous (sc) injection at this time
  6. Oral strontium ranelate 2gm daily stimulates bone formation and reduce fractures [1,61]
  7. Calcitonin is now considered third line; use for patients intolerant of other agents
  8. Combination Therapies
    1. Bisphosphonates may be added safely to calcium and vitamin D
    2. PTH and bisphosphonates should generally not be combined
  9. Monitoring Therapy [2]
    1. BMD often used to follow drug efficacy, though correlation with fracture risk is inexact
    2. Markers of bone turnover (such as Urinary N-Tx) can be used to assess acute effects
    3. BMD is useful for longer term effects on bone density
    4. In patients whose BMD decreases at year 1 on active therapy, recommend continuing treatment for additional year since >80% will have increases on BMD in year 2 [8]
    5. Current monitoring markers are poor for predicting fracture risk in individual patients
  10. Inhibition of RANKL [13]
    1. Denosumab, humanized monoclonal, blocks RANKL action
    2. RANKL required for osteoclast differentiation
    3. Denosumab sc treatment every 3-6 months for 1 year increased lumbar spine BMD similar to alendronate
    4. Denosumab reduced serum C-telopeptide and other markers of bone turnover
  11. Statins do not reduce fractures [9]

B. Calcium and Vitamin D navigator

  1. Overview [1]
    1. Overall meta-analysis of more than 63,000 patients shows significant fracture reduction with calcium 1200mg or more ± vitamin D 800 IU or more daily in age >50 years [34]
    2. At least two randomized studies have now shown no significant reduction in fractures in postmenopausal women taking calcium + Vit D versus placebo [11,12]
    3. Recommend at least 1200mg calcium + 800 IU vitamin D daily for women >50 years [34]
  2. Physicians should council patients to have adequate intake of calcium from diet
    1. Calcium Intake ~1000mg qd for post-menopausal women previously recommended [10]
    2. Improved bone density loss in women with low (<400mg/day) calcium intake
    3. In patients with history of urinary calcium stones, calcium citrate can be considered
    4. Supplemental calcium is of questionable benefit in persons with adequate dietery intake but overall is probably of benefit and well tolerated [34]
    5. Maintaining adequate Vit D and calcium maintains serum PTH in the (low) normal range [66]
  3. Vit D [27]
    1. Vit D supplements usually required in Northern climates to maintain normal levels [66]
    2. Normalizing Vit D levels allows reduction in required calcium supplementation [66]
    3. Consider measurement of vit D levels, especially in women >75 years
    4. Vit D supplements currently only recommended for persons with low serum levels
    5. Vit D supplementation with low serum levels should be 700-800U (18-20µg) per day
    6. Vit D 400 IU/day (+ calcium) is not sufficient to reduce risk of fractures [12]
    7. Vit D3 alone (mean calcium was 868mg/d from diet) did not reduce fractures
    8. Ergocalciferol 0.5mg/week is also effective
  4. Prevention of Fractures [10]
    1. Calcium+vit D did not reduce fractures in elderly with previous low-trauma fractures [11]
    2. Calcium+vit D showed an insignificant reduction in fractures in healthy postmenopausal women despite a small increase in hip bone density [12]
    3. Meta-analysis has shown 12% fracture reduction overall but 24% reduction with good compliance [34]
    4. Calcium+vit D increased risk of kidney stones by 17% [12]
  5. Calcium+vit D with Glucocorticoid Treatment
    1. Reduced risk of fractures in glucocorticoid treated patients
    2. Significant decreases in Serum PTH and plasma 1,25 dihydroxyvitamin D
    3. BMD increased in treated groups and decreased in controls on glucocorticoids
    4. Alendronate 10mg qd much more effective than Vit D (alfaclcidol) for prevention of bone loss in patients on glucocorticoids over 18 months [19]
  6. Recommend calcium + Vit D supplements after patient evaluation and education [1,34]

C. Bisphosphonate Therapy [33,64] navigator

  1. Generally first line treatment / second line prevention (after Vitamin D / Calcium)
    1. Stable analogs of pyrophosphate
    2. Bind to osteoclasts and/or bone sites and prevent resorption
  2. Generally well tolerated
    1. Esophagitis was common but now agents are taken with sufficient liquids to prevent this
    2. Jaw osteonecrosis has been reported rarely but must be considered [18]
  3. After 5 years of bisphosphonate, reasonable to take "drug holiday" for up to 5 years [3,71]
  4. Alendronate (Fosamax®) is most used, effective and well tolerated (see below) [62]
  5. Risedronate (Actonel®) [64]
    1. ~1000X more potent than etidronate, ~4X more potent than alendronate
    2. Negligible effects on bone formation
    3. Increases BMD in post-menopausal women with established vertebral fractures
    4. Maintained BMD increases over 7 year study [64]
    5. Very well tolerated in osteoporotic women >70 years
    6. Reduces both vertebral and non-vertebral (mainly hip) fractures fracture 30% [16]
    7. Rapid biochemical and symptomatic responses in patients with Paget Disease
    8. FDA approved for osteoporosis, 2.5-5.0mg/day
    9. Once weekly dosing (35mg) tablets now available [17]
    10. Side effects comparable to placebo (including esophagitis) [16]
  6. Zoledronic Acid (Zometa®, Reclast®) [24,42]
    1. Zometa® for hypercalcemia of malignancy and prevention of malignant bone metastases
    2. Reclast® for once yearly IV treatment of osteoporosis and for Paget's disease [42]
    3. Given as 15 minute IV infusion
    4. Dosing 4-5mg once yearly or 2mg q6 months IV improves BMD significantly
    5. Zoledronic acid 5mg IV given annually following a hip fracture, reduces risk of subsequent vertebral and nonvertebral fractures [25]
    6. Acute-phase reaction, usually with first infusion, with fever, headache, arthralgia reported
    7. Jaw osteonecrosis has been reported
  7. Tiludronate (Skelid®) [57]
    1. Bisphosphonate currently approved only for Paget's disease of the bone
    2. Dose is 400mg/day x 3 months
  8. Clodronate (Ostac®) [26]
    1. Novel bisphosphonate studied for use in osteoporosis as well as in breast cancer
    2. Clodronate reduces bone pain, hypercalcemia and pathologic fractures
    3. Clodronate also reduced new visceral (non-bone) metasteses (unclear mechanism)
    4. Clodronate also significantly reduced the mortality rate versus standard care alone
    5. Dose is 1600mg per day po
  9. Ibandronate (Boniva®) [65,70]
    1. Reduced new vertebral fractures in women with previous vertebral fracture 50% over 3 years
    2. No effect on non-vertebral fractures
    3. Oral dose is 2.5mg qd or 150mg po monthly
    4. Intravenous (IV) dosing approved for osteoporosis: 3mg IV q 3 months
    5. Similar side effect profile (except jaw claudication) to other bisphosphonates
    6. IV dosing may reduce esophageal side effects and for incapacitated persons who cannot remain upright for 30-60 minutes after taking oral bisphosphonates [70]
  10. Pamidronate (Aredia®) [22]
    1. Bisophosphonate available in intravenous and oral formulations
    2. Specifically inhibits bone resorption with little effect on bone formation
    3. Prevents glucocorticoid induced osteoporosis over 2 years
    4. After cessation of therapy, BMD is stable for >12 months
    5. Prevents osteoporosis due to androgen ablation therapy for prostate cancer [23]
    6. Prevents bone loss due to metastatic disease
    7. Reduces vertebral fractions in lymphoma patients receiving chemotherapy [63]
    8. Dose is typically 30-60mg IV q12 weeks
    9. Can cause esophagitis and other gastrointestinal upset
    10. Jaw osteonecrosis has been reported [18]
  11. Cyclic Etidronate Therapy
    1. Give 7-14d/month for up to 7 years significantly decreases osteopenia and fracture rate
    2. Minimal side effects at doses doses of 200-400mg per day intermittant every 3 months
    3. Effective with or without HRT/ERT in early post-menopausal period
    4. Osteomalacia did not develop over >7 years of therapy
    5. Etidronate for 14 days every 3 months reverses glucocorticoid effects on bone
    6. Recommendations for for prophylaxis against glucocorticoid induced osteoporosis below
  12. Glucocorticoid Induced Osteoporosis [68,69]
    1. Calcium and vitamin D should generally be given
    2. Mainstays are bisphosphonates ± anabolic agents [29,30]
    3. Bisphonates are clearly more effective than vit D alone and should be used [19]
    4. Alendronate 70mg/week or risedronate 35mg/wk are very effective
    5. Teriparatide (Forteo®) is more effective than alendronate for BMD increase and fracture preventation in patients on chronic glucocorticoids (see below) [53]
    6. For patients with or at high risk of fractures, teriparatide is strongly recommended

D. Alendronate (Fosamax®) [28]navigator

  1. 100 to 500 fold stronger inhibition of bone resorption compared to etidronate
  2. Utility
    1. One of the drugs of choice for treatment and prevention of common osteoporosis
    2. May be used alone or combined with other therapies
    3. Particularly in patients who refuse ERT or develop problems with calcium (such as kidney stones or hypercalcemia)
    4. Combination with full dose ERT/HRT provides improved BMD than either agent alone [30]
    5. Excellent for preventing and treating glucocorticoid induced bone loss
  3. Doses and Efficacy
    1. Significant BMD increases at 5-40mg po qd
    2. Three year trial showed ~50% reduction in new vertebral fractures, hip and wrist
    3. Three year trials, 1-5mg/d show clear, dose dependent effects [32]
    4. Four year primary prevention trial: 36% reduction in new vertebral fractures in women with BMD <2.5 below SD (osteoporosis) with 10mg/day
    5. Over 10 years, marked increases in BMD (10mg superior to 5mg qd), well tolerated [62,64]
    6. Dose 2.5-5mg/d prevents osteoporosis in post-menopausal women
    7. In women with existing vertebral fractures, 5-10mg/d reduces pain and days of bed rest [35]
    8. Efficacy of 2.5mg/d alendronate less than that of HRT [32]
    9. Original standard dose 10mg po qd; may increase to 20mg po qd
    10. Dosing 35-70mg weekly for prevention and 70mg weekly for treatment is effective
    11. Once-weekly 35 and 70mg dose pills are available [33]
    12. Take on empty stomach with plenty of water
  4. Adverse effects
    1. Major adverse effects are gastric upset, gastritis, esophagitis (dose dependent)
    2. Esophagitis is prevented by sitting upright and drinking lots of water with alendronate
    3. Alendronate 5mg po qd for 4 years had same incidence of esophagitis as placebo
    4. Jaw osteonecrosis is very rare
  5. BMD will begin declining ~6-24 months after cessation of alendronate [36,71]
    1. After 5 years of alendronate, BMD declindes slightly but no increase in fracture risk
    2. Unlikely that taking alendronate for >5 years will benefit most patients
  6. Recommend no more than 5 years of alendronate, followed by careful follow up [71]
  7. Once weekly alendronate (Fosamax®) 70mg prevents bone loss in men receiving hormone albation therapy [31]

E. Parathyroid Hormone (PTH) [3,37,38] navigator

  1. Intermittant therapy with subcutaneous PTH clearly increases bone mass
    1. Continuous PTH stimulates osteoclasts and blocks osteoblasts
    2. Intermittent (once daily) PTH peptides stimulate osteoclast and build bone
    3. Clear benefit to PTH: reduces lumbar spine bone loss and osteoporotic fractures [39]
  2. PTH is likely the most effective single agent increasing BMD, reducing fractures [40,41]
  3. Teriparatide (Forteo®) Therapy [37,43]
    1. Recombinant human PTH amino acids 1-34
    2. This represents active domain of the normal human 84 amino acid PTH polypeptide
    3. Given subcutaneously (20-40µg once daily) has 30 minute peak ikn serum, gone in 3-4 hours
    4. 20µg/day better tolerated and improved BMD more than 40µg/day doses
    5. Increased all skeletal bone mass and reduced vertebral fracture rates >50%
    6. Increased serum osteocalcin >55% in first 6 months
    7. Effective in women with osteoporosis or on GnRH therapy
    8. In women with osteoprosis, reduces new vertebral fractures 65%
    9. Reduces serious fractures and non-vertebral fractures
    10. Recommended dose is 20µg sc qd in thigh or abdomen for maximum of 2 years
    11. Strongly consider in patients treated with GnRH analogs or glucocorticoids who have fractures or continued osteoporosis with bisphosphonates [68,69]
    12. Teriparatide 20µg qd improves BMD and reduces vertebral fractures more than alendronate over 12-18 months in patients on chronic glucocorticoids [53]
  4. Teriparatide Prevents Osteoporosis in Women on GnRH analog therapy
    1. All patients with endometriosis
    2. They were treated with GnRH analog nafarelin (200µg intransally bid)
    3. Teriparatide 40µg qd x 6-12 months was very well tolerated
    4. Teriparatide had no effect on efficacy of GnRH therapy for endometriosis
    5. Spinal BMD decreased ~3% with nafarelin alone compared with increase ~3% with nafarelin combined with teriparatide
    6. Bone loss from femoral neck, trochanter and total body was prevented
    7. Bone turnover markers increased initially with teriparatide, then declined after 6-9 months
  5. Intact PTH (1-84) in Postmenopausal Women with Osteoporosis [29]
    1. Increased BMD at spine 6.9%, hip 2.1%, but reduced BMD in forearm
    2. Reduced vertebral fracture risk 40-60% versus placebo (primary and secondary cases)
    3. Increased hypercalciuria, hypercalemia, nausea relative to placebo
    4. Dose is 100µg recombinant intact PTH 1-84 daily sc (all women received Ca2+VitD)
  6. PTH combined with Alendronate [3,40,41]
    1. Intact PTH (1-84) 100µg sc qd improved volumes of both trabecular (vertebral) and cortical bone in women [40], but BMD decreased after cessation of PTH [67]
    2. PTH 1-34 37µg sc qd improved BMD in vertebrae and femoral neck better than alendronate in men [41]
    3. Combining alendronate with PTH therapy in both studies reduced PTH efficacy
    4. Likely that PTH stimulation of osteoblasts requires active osteoclasts
    5. Since bisphosphonates inhibit osteoclast function, PTH effect is reduced in combination
    6. Alendronate 10mg po qd following one year of intact PTH 100µg sc qd further increased bone density and prevented BMD reduction after PTH cessation [67]
    7. Three-month cycles of PTH 1-34 (25µg sc qd) followed by 3-months off PTH were as effective as daily PTH in poor alendronate responders [67]
    8. Cyclic or daily PTH 1-34 added to weekly aldendronate (70mg once weekly) increased BMD in patients with osteoporosis and poor response to alendronate [67]
  7. Side Effects
    1. Generally mild side effects included nausea and headache
    2. Dizziness and leg cramps can occur
    3. Mild hypercalcemia and hypercalciria can occur
    4. Avoid use in patients with increased risk of osteosarcoma
  8. Teriparatide is particularly effective in patients at high risk for fractures

F. Selective Estrogen Receptor Modulators (SERM) [44] navigator

  1. Raloxifene (Evista®) [45,46,47]
    1. Nonsteroidal benzothiophene with selective estrogen receptor interactions
    2. Agonist effects on bone and apparently vascular endothelium
    3. Improves lipid profiles with reduction in LDL and some increases in HDL
    4. Antagonist effects on uterus, without causing endometrial hyperplasia
    5. Reduces new vertebral fractures by 50% in women with or without previous fractures
    6. Similar efficacy as alendronate, risedronate, raloxifene on nonvertebral fractures [15]
    7. Clearly improves bone density at vertebral and non-vertebral sites
    8. Reduces cardiovascular events 40% in high risk women with osteoporosis [48]
    9. Does not alter nor improve cognitive function in postmenopausal osteoporotic women [49]
    10. Initial data show >50% reduction in new invasive breast cancer with 4 years use [50]
    11. Differential effects of raloxifene versus estrogen likely due to distinct interactions with specific domains of the estrogen receptor (ER) called AF-1 and AF-2
    12. In addition, a second ER has been discovered and may play a role in these differences
    13. Increases risk of venous thromboembolism ~3X (similar to estrogens and tamoxifen)
    14. Does not cause vaginal bleeding or uterine hyperplasia
    15. FDA approved postmenopausal osteoporosis dose is 60mg po qd (30-150mg available)
  2. Experimental Agents [36]
    1. Tamoxifen (TAM, Nolvadex®) - approved for breast cancer; stimulates bone formation
    2. Droloxifene
    3. Idoxifene
    4. Levormeloxifene

G. Hormone Replacement Therapy (HRT/ERT) [36]navigator

  1. Recommendations for HRT [6,7]
    1. Standard dose HRT is no longer generally recommended for post-menopausal women
    2. ERT/HRT improves osteoporosis, but increases cardiovascular events and possible cancer
    3. ERT/HRT should only be considered in women with significant menopausal symptoms
    4. SERMs such as raloxifene and tamoxifen increase BMD and reduce cancer risk [45]
    5. Lower dose estrogen (0.3mg/d conjugated) may be used and has reduced risks
    6. Lose dose estrogen patch (Menostar®) has good efficacy, may have reduced side effects [20]
  2. Efficacy of ERT in Prevention of Osteoporosis
    1. In prospective study of full dose combination HRT, reduced fractures in all subgroups [60]
    2. Very effective in older, very frail women [51]
    3. Both spinal and non-spinal fractures reduced, even in >70 year olds
    4. Significant reduction of nonvertebral fractures >27% overall [52]
    5. All types of HRT reduced fractures overall 38% during use; protection begins rapidly on initiation of therapy and disappears rapidly after use ceases [58]
    6. Combination HRT with alendronate increased BMD more than either component alone [30]
  3. ERT Dosages [36]
    1. Concern over side effects and poor risk:benefit have reduced full-strength ERT use
    2. Original doses of 0.625 mg conjugated estrogen (such as Premarin®) or estinyl estradiol 20µg po qd are no longer recommended due to side effects
    3. Lower doses of ERT (0.325mg qd) are as effective with reduced side effects
    4. Low dose continuous combination HRT is very effective and well tolerated [54]
    5. Unopposed low dose (0.3mg/d) estrogen has desirable bone and lipid effects without causing endometrial hyperplasia
    6. Calcium added to low dose 0.325mg/d estrogen effective for preventing osteoporosis
    7. Ultralow dose micronized 17ß-estradiol (0.25mg/d) improved BMD and reduced bone turnover markers with minimal adverse effects [55]
    8. Conjugated estrogens 0.45 or 0.3 mg qd, with or without medroxyprogesterone (MPA), increase BMD and improve markers of bone turnover in early post-menopause [54,56]
    9. MPA 2.5mg qd continuous is effective as added progesterone for intact uterus [60]
    10. Transdermal estrogen patch is effective and may provide more constant estrogen levels
    11. Most transdermal patches deliver 25-50µg/d estrogen
    12. Low dose estrogen patch (Menostar®) delivers 14µg/d 17ß-estradiol and is well tolerated with good improvements in BMD [20]
    13. For women with an intact uterus, a progesterone should be added (for both oral or patch)
    14. Phytoestrogens may be taken orally and may be safer than ERT/HRT overall
    15. Genistein, a phytoestrogen, 54mg qd x 2 years, improves BMD and bone markers [72]
    16. Genistein had no effect on uterine wall thickness after 2 years
  4. Contraindications
    1. Women with breast cancer or ovarian cancer
    2. Women with a family history of breast or uterine cancers (relative contraindication)
    3. Migraines
    4. Unexplained vaginal bleeding
    5. Recent vascular thrombosis
    6. Combination may lead to restoration of periods
    7. TAM or raloxifene may be acceptable for women with family cancer histories [36]

H. Calcitonin (Miacalcin®) navigator

  1. Inhibits bone resorption (and formation)
  2. Blocks osteoclast function and has analgesic properties (probably at opiate receptor)
  3. May be effective in preventing or arresting osteoporosis
  4. Not as effective as bisphosphonates or raloxifene [15]
  5. Nasal Calcitonin [59]
    1. Prevents lumbar spine bone loss and reduces vertebral fractures
    2. Efficacy is minimal, however, and 200U dose was only effective dose in large study [59]
    3. Dose is 50-200U nasal qd 5 days/week
    4. 50U/d prevented lumbar spine bone loss but no significant increase in BMD
    5. 200U/d increased bone density in lumbar spine 2-3% over two years
    6. Well tolerated; no changes in biochemical parameters of bone loss
    7. 200U/d reduced fractures and has analgesic properties
    8. No change in BMD at hip sites, however
    9. Extremely well tolerated; main side effect is nasal irritation

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