Evidence-based Medicine Resources in Current and Alternative Therapies
Compiled by: Constantine Kaniklidis, medical researcher
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Home    Osteoporosis Watch:  Evidence-based Treatment of Osteoporosis  [updated: 03/16/2007]
This site is dedicated to the loving memory of Anne Lowenthal*
 

Osteoporosis - Treatment Standard


  • The Treatment Standard:
    Besides critical non-pharmacological parameters (such as exercise, optimal nutrition and weight control, avoidance of smoking, excessive alcohol, and glucocorticoids), clinical focus for the treatment of osteoporosis has been on pharmacological agents which exert their effects by either
    (1) inhibition of bone resorption (antiresorptive agents) with an associated gain in bone mass, or
    (2) direct anabolic activity (anabolic agents);
    both pathways may be associated by an enhancement in bone strength and bone quality.
    Besides BMD (bone mineral density), there are several easily measured risk factors for osteoporotic fracture prediction: low body weight, current smoking, and age between 75–79 years being the most evidenced (Bensen et al. (BMC Musculoskelet Disord (2005): Evaluation of easily measured risk factors in the prediction of osteoporotic fractures)).

    It should be noted that cumulative EBM (evidence-based medicine) findings have demonstrated that BMD (bone mineral density) alone does not predict response to treatment for osteoporosis and that BMD increases may not correlate directly with a fracture reduction; in particular, in work of Watts et al. (J Clin Densitom (2004):
    Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk) clarified that although patients showing an increase in BMD had a lower fracture risk than patients showing a decrease in BMD, greater increases in BMD did not necessarily predict greater decreases in fracture risk.

  • Bone Markers and BMD:
    Although D(E)XA bone densitometry is the current established standard for measuring bone mineral density (BMD), measures of bone turnover rate have matured to the point of valuable adjuncts in osteoporotic disease and treatment efficacy assessment. Several bone turnover markers have been proposed but most are non-specific and non-optimal, being the break down products of various collagenous tissues; of these it appears that N-telopeptide (NTx) accurately monitors bone resorption since it is derived from type 1 collagen found only in bone. Therefore, NTx (urinary N-telopeptide), a marker of bone resorption, may be a clinically viable measure, with elevation of this value (>40 nmol bone collagen equivalent per mmol urinary creatine) typically indicating a high turnover state.

    See Xue et al. (Chin Med J (1999):
    Urinary cross-linked N-telopeptides of type I collagen and bone metabolic diseases) found that NTx in urine is a specific and sensitive indicator of bone resorption and is able to distinguish normal premenopause from late osteoporotic patients, therefore allowing monitoring of antiresorptive therapy; Chaki et al. (J Bone Miner Res (2000): The predictive value of biochemical markers of bone turnover for bone mineral density in postmenopausal Japanese women) concluded that baseline urinary NTx was the most sensitive predictor of bone loss in the lumbar spine, allowing such markers of bone resorption to be used clinically to predict future BMD in postmenopausal women; Ravn et al. (Bone (1999): Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women. Alendronate Osteoporosis Prevention Study Group) found that sensitive biochemical markers offered a fast and valid alternative to bone densitometry for monitoring of alendronate treatment; Maugeri et al. (Arch Gerontol Geriatr (2000): The NTX assay in the follow-up of the osteoporotic patients: 3 years of alendronate treatment) who found that monitoring of urine NTx levels are useful during antiosteoporotic treatments due to the fact that a reduction of NTx is an indicator of the slowing down of bone turnover and bone losses; Dogan & Posaci (Postgrad Med J (2002): Monitoring hormone replacement therapy by biochemical markers of bone metabolism in menopausal women) also found biochemical markers of bone to reflect acute changes in bone turnover rate and hence allow changes in marker levels to be used to monitor the effectiveness of osteoporosis therapy, with NTx, CTx, and osteocalcin being the most promising markers.


  • Antiresorptives:
    Evidence based reviews of treatments for postmenopausal osteoporosis have confirmed which treatments reduce the risk of fractures in women with osteoporosis. Most currently used drugs are antiresorptive agents that reduce osteoclast mediated resorption and bone remodelling (loosely, osteoblasts are bone-building cells, and osteoclasts are bone-breakdown or resorption cells). The major classes of agents inhibiting bone resorption are: (1) bisphosphonates, (2) calcitonin, (3) SERMs (selective estrogen receptor modulators), (4) estrogen, (5) calcium + Vitamin D.

  • Anabolic Agents:
    Parathyroid hormone (PTH), as teriparatide [Recombinant Human Parathyroid Hormone (1-34)] has become available as the first anabolic bone agent; an alternate full-length human PTH anti-oseoporotic drug, PREOS, is in the pipeline for possible introduction by approx 2005. See our separate comprehensive coverage on
    Bone Rebuilding (Osteoformative) Agents: PTH.

  • Potent Bisphosphonates:
    These include alendronate (Fosamax) )and risedronate (Actonel), which reduce the relative risk of vertebral fractures by 40-50%. Both of these bisphosphonates also reduce the relative risk of non-vertebral (peripheral) fractures (for example, fractures of the hip and wrist) by 40-50% and are now considered to be first line agents for the prevention and treatment of postmenopausal osteoporosis. The advent of weekly alendronate and risedronate treatment has made bisphosphonate treatment more convenient. In clinical trials the most commonly reported adverse events were chest and abdominal pain, and GI distress (dyspepsia and nausea).

    Zoledronic acid (Zometa), pamidronate (Aredia), and ibandronate (Boniva) are new bisphosphonates (see our section on Osteoporosis: New Frontiers).

  • Osteoporosis Watch Commentary:
    Evidence-based studies of sufficient power have not yet appeared to truly determine optimal duration of treatment for the bisphosphonates, especially given their long bone half-life (years). The JCEM study of Tonino et al suggests that despite established safety of alendronate out to 7 years, BMD and bone turn-over marker benefits may not extend past 5 years. However, the recent work of Sambrook et al (Osteoporosis Int: Alendronate in the Prevention of Osteoporosis: 7-year follow-up) suggests that continuous dosing at 5 or 10 mg daily for up to 7 years increases BMD in recently postmenopausal women, with greater gains at 10 mg, and a BMD penalty associated with early discontinuation; and Rodan et al. (Curr Med Res Opin (2004): Bone safety of long-term bisphosphonate treatment) in a recent review have identified only beneficial BP effects on bone of bisphosphonates in controlled trials of up to 10 years follow. And it should be noted that at least for vertebral fractures, alendronate decreases the risk in men (Sawka et al. (BMC Musculoskelet Disord (2005): Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women) as well as in women at risk.

    Thus although definitive sufficiently powered studies have not appeared to determine long-term consequences of bisphosphonate-induced bone retention on the biomechanical properties of bone, most experts appear to agree that concerns about bone turnover oversuppression and microdamage accumulation remain largely theoretical and to date without clinical basis for discontinuation (see the work of Miller in Expert Opin Pharmacother:
    Efficacy and Safety of Long-term Bisphosphonates in Postmenopausal Osteoporosis).

  • SERMs - Raloxifene (Evista):
    The selective estrogen receptor modulator raloxifene (Evista) produces smaller increases in bone mineral density than other treatments but reduces the risk of vertebral fractures by 36%. However, evidence for its effect on non-vertebral fractures is weak. Furthermore, raloxifene's effect on the hip is to date equivocal. Thus although Liu et al. (Chin Med J (2004):
    Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial) found that raloxifene affected vertebral and hip BMD significantly, hip fracture reduction did not achieve statistical significance despite the increase in hip BMD.

    Indeed, the report card to date on the traditional osteoporosis therapies is:

    • Hormone therapy, alendronate (Fosamax) and risedronate (Actonel) have been shown to reduce all fracture risks: vertebral and non-vertebral, including hip.

    • Parathyroid hormone, PTH (Teriparatide (Forteo)) evidences vertebral and non-vertebral, but not hip, fracture reduction.

    • Calcitonin (Miacalcin) and raloxifene (Evista) evidence only vertebral fracture, and not non-vertebral or hip, reduction.


    Studies appear to confirm that SERMs effect a significant decrease in the number of new cases of breast cancer, acting, like tamoxifen, as an estrogen antagonist in breast tissue through competitive binding to the estrogen receptor (and raloxifene in particular appears to have no negative impact of either breast or endometrial cell proliferation). In addition, unlike HRT, SERMs may either aggravate or, more probably, at least not benefit the menopausal symptom of hot flashes.

    It appears to be not uncommon clinical practice to switch to raloxifene from alendronate when upper GI adverse effects are suspected. Osteoporosis Watch finds no basis in the evidence for this practice, and indeed, Luckey et al. (Menopause (2004): Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis) found no significant differences in the incidence of upper gastrointestinal adverse experiences between alendronate and raloxifene, and alendronate induced significantly greater increases in lumbar spine and hip BMD, with greater reductions in bone turnover markers on alendronate.

    SERMs, inlcuding raloxifene, like HRT, increase the risk of venous thromboembolism, which encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE).

  • Calcitonin:
    The evidence for nasal calcitonin, a polypeptide hormone, for preventing vertebral fractures is weak owing to inconsistency of effect across various doses, and large follow up losses of patients in the largest trial (see Endocrine Review: Summary of Meta-Analyses of Therapies for Postmenopausal Osteoporosis). There is, however, some evidence of a significant analgesic effect, but there is no clear evidence that nasal calcitonin reduces non-vertebral fractures. (See also the recent comprehensive review in Endocrinol Metab Clin North Am: Calcitonin).

  • Osteoporosis Watch Commentary:
    Given that calcitonin is a biological agent (whereas bisphosphonates are inorganic agents exhibiting direct binding to bone) there is some question of potential clinical resistance, especially after long-term treatment, secondary to antibody presence or possibly downregulation; since calcitonin receptors appear to return after a calcitonin "drug holiday", this may suggest exploration of some intermittent regimen to minimize possible clinical resistance.
    Couple this with (1) the weak and inconsistent evidence of efficacy in vertebral fractures, and (2) the lack of clear evidence in non-vertebral fracture reduction, Osteoporosis Watch believes the role of calcitonin in anti-osteoporotic therapy needs to be critical reassessed, and it should not until that time play other than a secondary adjuvant status when other well-established agents serve as first-line primary therapies, possibly for leveraging an analgesic effect from calcitonin; it may also be prudent to deploy some drug holiday regimen, for reasons previously cited.


  • Vitamin D:
    Vitamin D is known to be essential for calcium absorption (in the stomach and gastrointestinal tract) into the bone, as well as for normal bone growth, and as a vitamin exhibits hormonal-like activity: lower levels may impair calcium absorption, and this in turn increases parathyroid hormone (PTH), where high PTH levels (and low levels of vitamin D ) are associated with hip fracture in menopausal women, as persistently high levels of PTH stimulate bone loss via bone resorption.

    Given that a primary source for vitamin D is the sunlight's photochemical effect on the skin, bone formation is known to peak in summer while bone breakdown increases in winter. From this, and the fact that vitamin D levels decline with age (Gaugris et al. (QJM (2005): Vitamin D inadequacy among post-menopausal women: a systematic review) found the prevalence of inadequate vitamin D levels appears to be high in post-menopausal women), supplementation to yield total at least 800 IU (20 mcg.) daily would appear prudent (Vieth et al., J Steroid Biochem Mol Biol (2004): Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults). Indeed Stefikova et al. (Vnitr Lek (2004): Intensive vitamin D supplementation in the treatment of osteoporosis) evaluated the efficacy and safety of 15,000 IU/week vitamin D (approx. 2100 IU daily) in postmenopausal women with osteopenia or osteoporosis, finding no adverse consequences or clinical hypercalcemia. And it appears that levels of supplementation lower than 800IU / daily are not consistently effective (Vieth, (Ann Med (2005):
    The role of vitamin D in the prevention of osteoporosis).

    Indeed, it may be that annually recurring cycles of low vitamin D during winter months is a partial contributor to age-related bone loss over the longterm; thus Meier et al. (J Bone Miner Res: Supplementation With Oral Vitamin D3 and Calcium During Winter Prevents Seasonal Bone Loss: A Randomized Controlled Open-Label Prospective Trial) found supplementation with oral vitamin D3 and calcium (oral cholecalciferol (500 IU/day) and calcium (500 mg/day)) during winter abolished seasonal changes in calciotropic hormones and markers of bone turnover and led to an increase in BMD and thus may be beneficial as a primary prevention strategy for age-related bone loss. And at least for bone mineral augmentation in adolescent girls, a dose level of Vitamin D3 at 400 IU (mg) was necessary to increased both femur (hip) lumbar spine BMC augmentation significantly, the lower 200 IUs (mg) dose not significantly affecting the lumbar spine (Viljakainen et al. J Bone Miner Res (2006): A Positive Dose–Response Effect of Vitamin D Supplementation on Site-Specific Bone Mineral Augmentation in Adolescent Girls: A Double-Blinded Randomized Placebo-Controlled 1-Year Intervention).

    Note that although some prescription forms of vitamin D (such as calcitriol) are available for osteoporotic treatment, they may precipitate hypercalcemia (high blood calcium levels) and so require frequent monitoring. However, one form, alfacalcidol, was found to exert higher bone-protective effects than standard vitamin D3, with therefore the potential for dose reduction and minimization of the risk of adverse effects, especially hypercalcemia (Reginster et al., Rheumatol Suppl (2005): Importance of Alfacalcidol in Clinical Conditions Characterized by High Rate of Bone Loss), and it appears to not only exhibit anti-fracture efficacy but also efficacy in the prevention of falls (Orimo & Schacht, Rheumatol Suppl (2005): The D-Hormone Analog Alfacalcidol: The Pioneer Beyond the Horizon of Osteoporosis Treatment).

    And other well-designed RCTs have found for positive benefit: Heike Bischoff and colleagues (Bischoff et al., J Bone Miner Res (2003): Effects of Vitamin D and Calcium Supplementation on Falls: A Randomized Controlled Trial) demonstrated that Cal+D-treatment accounted for a 49% reduction of falls compared to calcium alone, possibly consequent to an observed improvement in musculoskeletal function. And the same author (Heike Bischoff-Ferrari) and colleagues concluded from their meta-analsysis (JAMA (2005): Fracture Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized Controlled Trials) that "oral vitamin D supplementation between 700 to 800 IU/d appears to reduce the risk of hip and any nonvertebral fractures in ambulatory or institutionalized elderly persons. An oral vitamin D dose of 400 IU/d is not sufficient for fracture prevention". This has been recently further confirmed in a dose determination study of Heike Bischoff-Ferrari (Osteoporosis Int (2006): How to select the doses of vitamin D in the management of osteoporosis) who concluded that "the dose of vitamin D in the management of osteoporosis should be no less than 700–800 IU per day".


  • Calcium Supplementation:
    Randomized controlled trials have confirmed that calcium (min. 1000mg/daily) and vitamin D (at least 1000 IU/daily, equivalent to 20 mcg.) in combination can reduce the risk of hip and non-vertebral fractures in elderly people. Note that although the widely reported RECORD (Randomised Evaluation of Calcium Or vitamin D) and the WHI (Women’s Health Initiative) trials have concluded that the effectiveness of calcium and vitamin D alone in hip fracture prevention is unclear, this appears to be in error, as a careful meta-analysis of 4 major RCTS, including these two trials, by S. Boonen and colleagues (Boonen et al., American Society for Bone and Mineral Research - ASBMR Annual Meeting (2006): Evidence for Hip Fracture Risk Reduction with Calcium and Vitamin D from a Comparative Meta-Analysis of Randomized Controlled Trials Including RECORD and WHI) found that oral vitamin D supplementation reduces the risk of hip fractures when calcium supplementation is added, even when taking into account recent negative trials like RECORD and WHI.

    Furthermore, it should be noted that the WHI findings (Jackson et al., N Engl J Med (2006): Calcium plus vitamin D supplementation and the risk of fractures) are wholly suspect given profound methodological flaws:

    (1) low compliance - by study termination, only 41% of the subjects were compliant with the levels of calcium and Vitamin D prescribed by the study's intervention regimen, with 24% discontinuing the supplements completely;
    (2) those subjects who dis, however, remain largely compliant nonetheless achieved a statistically significant 29% fracture reduction;
    (3) inadequate dose of Vitamin D - the trial used 400 IU/daily, known (see our discussion of Vitamin D above) to be insufficient;
    (4) confounding factor of HRT use - the majority of subjects in both the control and the intervention arm were on estrogen hormone therapy;
    (5) low solubility and low bioavailability calcium carbonate was used, rather than a more efficient calcium citrate preparation;
    (6) subjects were allowed to take supplemental calciuma (up to 1000 mg/daily) and/or vitamin D (up to 1000 IU/daily) on their own, regardless of whether they were allocated to the Calcium+D group or the placebo group;
    (7) the baseline calcium intake of most subjects appears to have been near or above that threshold, leaving therefore little opportunity for benefit and effectively nullifying the concept of an untreated placebo group for calcium consumption;
    (8) and over 15% of the subjects used anti-osteoporosis drugs, primarily bisphosphonates;
    (9) most participants were likely to be at low risk for osteoporotic fractures given: high BMI, estrogen replacement, adequate calcium intake, and normal hip T-score, and a significant subset of participants were also taking bisphosphonates.

    These and other serious compromises in design methodology and implementation discard the WHI as an invalid test of the hypothesis being tested (as also demonstrated by Robert Heaney in his editorial on these issues and the WHI trial in particular: Am J Clin Nutr (2006): Nutrition, chronic disease, and the problem of proof), and Janet Barger-Lux and Robert Recker concluded in their critique of the WHI trial (BoneKEy-Osteovision (2006): Calcium, Vitamin D, and Fractures in the WHI Data) and its findings that "those who did read the fine print could discern that the data did not shed very much light on the clinical question. In fact, we believe that the limitations of this study all but negate its validity".

    It would now appear that calcium and fruit and vegetable-based nutrients (vitamin C, magnesium, and potassium (and possibly modest alcohol intake)), are favorable to BMD, while polyunsaturated fatty acids are highly unfavorable, at least in a premenopausal context (see MacDonald et al in Am J Clin Nutr:
    Nutritional Associations with Bone Loss during the Menopausal Transition), and these findings on BMD and lipids are supported by the work of Adami et al (Calcif Tissue Int: Relationship between Lipids and Bone Mass in 2 Cohorts of Healthy Women and Men).

    Timing of calcium supplement intake is critical. Calcium absorption is maximized by ingestion with meals by virtue of gastic emptying being slowed, hence improving the efficiency of calcium absorption, further enhanced by speading the calcium ingestion throughout the day.
    This optimal timing stratgey of calcium, however, compromises phosphorus absorption by maximizing phosphorus binding (Schiller et al, N Engl J Med: Effect of the time of administration of calcium acetate on phosphorus
    binding
    ).

    Finally, in terms of optimal form of calcium supplementation, calcium citrate decreased several critical markers of biochemical bone resorption (N-telopeptide, C-telopeptide, free deoxypyridinoline, and serum N-telopeptide) while calcium carbonate left these unaffected (Kenny et al., Osteoporosis Int (2004): Comparison of the effects of calcium loading with calcium citrate or calcium carbonate on bone turnover in postmenopausal women). Given this only calcium phosphate (see below) appears to have any potential for challenging this biochemical advantage of calcium citrate, with the possible exception of calcium formate in terms of bioavailability: Hanzlik et al. (J Pharmacol Exp Ther (2005): Relative Bioavailability of Calcium from Calcium Formate, Calcium Citrate, and Calcium Carbonate) and colleagues conducted a four-way crossover study using either a placebo or 1200 mg of calcium as calcium carbonate, calcium citrate, or calcium formate: calcium formate was significantly superior to both calcium carbonate and calcium citrate in ability to deliver calcium to the bloodstream after oral administration. Calcium formate may offer significant advantages as a dietary calcium supplement

  • A Note on Magnesium:
    The requirement of the nutrient magnesium for cell metabolic activity is well-known. Yet as to its role in osteoporotic therapy, the balance of the evidence is currently that the benefits of calcium incur without any magnesium supplementation (Menopause (2002):
    Management of postmenopausal osteoporosis: position statement of the North American Menopause Society [pdf]), so normal dietary levels appear to be sufficient in this context (Spencer et al., J Am Coll Nutr (1994): Effect of magnesium on the intestinal absorption of calcium in man).

    Note however that certain special classes of patients may require magnesium supplementation: frail, elderly women, and women with gastrointestinal disease (Durlach et al., Magnes Res (1998):
    Magnesium status and ageing: an update).

    Furthermore, there may be a positive effect of magnesium supplementation (300 mg elemental magnesium/daily in two divided doses) on integrated hip bone mineral content (BMC), at least for adolescent females (Carpenter et al., J Clin Endocrinol Metab (2006): A Randomized Controlled Study of Effects of Dietary Magnesium Oxide Supplementation on Bone Mineral Content in Healthy Girls).

  • Phosphorus:
    Despite the common misperception that bone mineral is (just) calcium, bone mineral consists of calcium phosphate, and accummulating evidence suggests that phosphorus may be as critical as calcium for bone health. The recent study by Heaney (Mayo Clin Proc:
    Phosphorus Nutrition and the Treatment of Osteoporosis) suggests that 10 to 15% of the elderly may have below-RDA intake of this critical mineral, aggravated by using high-dose carbonate or citrate salt calcium supplements which may bind the phosphorus in the gut, hence rendering it unavailable for absorption, with the consequence that the resulting depressed phosphorus level may be insufficient to support substantial bone rebuilding; it has been determined that each 500mg of ingested calcium binds 166mg of dietary phosphorus. We know that at new bone-forming sites, hypophosphatemia constrains mineralization, and regardless of cause, this condition further compromises osteoblast (bone-building cell) function as well as enhancing the osteoclast (bone breakdown) resorption process (Raisz et al., Endocrinol: Effect of phosphate, calcium and magnesium on bone resorption and hormonal responses in tissue culture [pdf]). And effective antiresorptive osteoporotic therapies increase phosphorus requirements and may therefore aggravate any deficiency, while anabolic osteoporotic therapies (teriparatide) are even more demanding.

    In this context, the study concludes that calcium phosphate supplements may have an advantage over carbonate / citrate salts in a phorphorus-sparing mode. Indeed, Heaney and Nordin (J Am Coll Nutr (2004):
    Calcium Effects on Phosphorus Absorption: Implications for the Prevention and Co-Therapy of Osteoporosis) found that under calcium intake increases without corresponding increases in phosphorus intake, phosphorus absorption is reduced, and consequently the risk of phosphorus insufficiency increases, especially likely with substantial intake of non-phosphate calcium salts.

    For this reason, they recommend that older osteoporotic patients receive at least some of their calcium co-therapy in the form of a calcium phosphate preparation. This form of coingested calcium/phosphorus serves double duty of providing the requisite calcium and sparing food phosphorus.

    However, as noted above in our discussion of calcium, the optimal timing of calcium supplement intake - with meals and distributed throughout the day - compromises phosphorus absorption by maximizing phosphorus binding (Schiller et al, N Engl J Med:
    Effect of the time of administration of calcium acetate on phosphorus binding).

    In addition, it must be noted even for women who are not being treated with osteoporotic therapies, a negative phosphorus balance can incur under conditions of high calcium supplementation (distributed doses of 1500 mg in daily mealtime dividied doses, or greater), especialy if meat and dairy intake is low.

    Warning: The work of Heaney & Nordin cited above, found that anabolic agents like teriparatide (Forteo) places special demands on phosphorus intake, in that calcium supplementation with carbonate or citrate salts in excess of 1200 mg/daily is sufficient to induce a situation in which effectively no dietary phosphorus is available to support bone building. This is due primarily to the fact that - as cited in the Heaney study above - the phosphorus demand to support bone mineralization is of the order of ten times that of antiresorptive therapy the inherent parathyroid hormone activity of teriparatide lowers the renal phosphorus threshold, and consequently also the serum inorganic phosphorus level). In such an especial circumstance use of a calcium phosphate supplement would be more than prudent, almost imperative unless demanding, possibly unrealistic, changes to the diet are countenanced.

  • Vitamin K:
    In addition, vitamin K may also be critical for bone protection and fracture prevention, given that is requisite to the production of the bone protein, osteocalcin (osteocalcin is a strong indicator of osteoblastic - bone-building - activity). Supplementation is typically with Vitamin K2 (menatetrenone (aalso known as menaquinone), at 150 - 200 mcg., up to 450 mcg., useful for fracture prevention in osteoporotic patients, but with appropriate care being exercised given the known effect of vitamin K on blood clotting (patients on coumadin or similar anticoagulants may require dose adjustment as dictated by INR test values).

    As to vitamin K daily requirement, see the study of Booth et al., J. Nutr.:
    Dietary Phylloquinone Depletion and Repletion in Older Women, which concluded that the current recommended intake of vitamin K of 90 mcg daily is likely to be sub-optimal in terms of bone health, as this is not sufficient to support optimal osteocalcin production by elderly women, requiring instead 200 - 450 mcg. daily. Also Ryan-Harshman & Aldoori (Can Fam Physician: Bone health. New role for vitamin K?) concluded that dietary Vitamin K intake of <100 µg daily might not be optimal for bone health, and that such low intake of vitamin K could contribute to osteoporosis and subsequent fracture (due to the undercarboxylation of osteocalcin). This is further supported by the UK's FSA (Food Standard Agency) Intervention Study N05001 which found a statistically significant increase in BMD for the combined vitamin D + calcium + vitamin K (at 200 mcg.) supplemented study group.

    Furthermore, it appears that Vitamin K supplementation benefits femoral neck BMD in particular: If co-administered with minerals and vitamin D, vitamin K1 may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck (Braam et al., Calcif Tissue Int (2003):
    Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age) when given at the level of 1 mg./daily (1000 micrograms) in conjunction with 8 mcg. Vitamin D.

    Finally a recent systematic review and meta-analysis of fracture risk reduction and Vitamin K (Cockayne et al., Arch Int Med (2006): Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials) has provide a determination of optimal form of Vitamin K: 11 of 13 reviewed trials used menaquinone-4 (Vitamin K2), and in 10 of these 11 trials, the dose was 45 mg/day. Given these findings, coupled with the above-cited dose determination studies of Booth, Ryan-Harshman & Aldoori, and the UK Food Standard Agency (FSA, Osteoporosis Watch suggest that an more optimal dose level for anti-ostoporotic activity, BMD, and fracture risk reduction would be at least 200 mcg/daily of Vitamin K, as the K2 form.

    Note that anyone on anticoagulant therapy (for instance, warfarin (Coumadin)) should discuss Vitamin K supplementation with their physician, as careful monitoring of INR values, among others, may be required to assure the proper adjusted dose of the anticoafgulant agent, since interaction with anticoagulant activity by Vitamin K is possible. However, contrary to common concerns, low-dose vitamin K may actually facilitate smoothing out the oft-encountered variability in INR caused by warfarin, without creating excessive coagulation, as found a a small series conducted at the University of Texas in 2005 (Reese et al., Pharmacother (2005): Low-Dose Vitamin K to Augment Anticoagulation Control) where it was found that supplementation with daily low-dose oral vitamin K significantly increased the number of INRs in range as well as the time in range, and decreased INR fluctuation in this small series of selected patients.

    Note:
    It is significant to note that neither dietary nor supplemental calcium alone evidenced a positive effect on BMD, suggesting a critical interaction between vitamins D + calcium and K in bone loss reduction. Further, the researchers found evidence for sub-optimal vitamin D and vitamin K status in a large proportion of the healthy older women who took part in this study, suggesting that current guidelines are, with respct to optimal bone health, too conservative, especially in the elderly and in populations at risk of osteoporosis.

  • Folate / Vitamin B12 / Homocysteine:
    The recent work of Cagnacci (Bone:
    Relation of Homocysteine, Folate, and Vitamin B12 to Bone Mineral Density of Postmenopausal Women), suggests a significant association between folate and bone mineralization. Given that vitamin B12 is important to DNA synthesis, being linked to osteoblastic activity, and hence may affect bone formation, Tucker et al. (J Bone Miner Res (2005): Low Plasma Vitamin B(12) Is Associated With Lower BMD: The Framingham Osteoporosis Study) decided to examined the relationship between plasma vitamin B12 status and BMD in the Framingham Offspring Osteoporosis Study (1996-2001); they found that both men and women with low vitamin B12 concentrations (<148 pM) had lower average BMD than those above this cut-off, concluding that vitamin B12 deficiency may be an important modifiable risk factor for osteoporosis.

    More recently, two studies published in NEJM have together established elevated homocysteine as a risk factor in osteoporotic fractures.The van Meurs et al study (N Engl J Med:
    Homocysteine Levels and the Risk of Osteoporotic Fracture) concluded that "increased homocysteine level appears to be a strong and independent risk factor for osteoporotic fractures in older men and women". The MacLean et al study (N Engl J Med: Homocysteine as a Predictive Factor for Hip Fracture in Older Persons) examined the association between total homocysteine concentration and risk of hip fracture (in men and women enrolled in the Framingham (heart) study), concluding that homocysteine concentration . . . is an important risk factor for hip fracture in older persons".

    Finally, this has been directly confirmed by Paul Gerdhem and colleagues (Gerdhem et al., J Bone Miner Dis (2007):
    Associations Between Homocysteine, Bone Turnover, BMD, Mortality, and Fracture Risk in Elderly Women) who found that in 996 women from the OPRA (Osteoporosis Population-based Risk Assessment) study, high homocysteine level was associated with higher bone turnover, poor physical performance, and lower BMD, and also with mortality during a mean 7-year follow-up, but there was no clear association with fracture risk.


  • Osteoporosis Watch Commentary:
    Although the studies cited above do not establish a causal relationship between elevated homocysteine levels and osteoporotic fracture risk, only an association, Osteoporosis Watch nonetheless believes that (1) despite some methodological issues with these homocysteine studies, elevated homocysteine level does appear strongly indicative of osteoporotic risk fracture, and (2) these studies are cross-confirmative with the conclusions of Cagnacci, cited above, with respect to the significant association between folate and BMD, given that it is well established that increased folate / folic acid intake modulates and decreases circulating homocysteine levels. See Herrmann et al., Clin Chem Lab Med (2005): Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women who found a weak, but significant, relations between homocysteine and markers of organic and inorganic bone resorption, suggesting a mechanistic role in bone metabolism, so that from initial experimental results it would appear that homocysteine is not only a risk indicator, but also a player in bone metabolism. See also Hermann et al. (Clin Chem Lab Med (2005): Homocysteine – a newly recognised risk factor for osteoporosis) who concluded from recent data that homocysteine, folate, vitamin B6 and vitamin B12 affect bone metabolism, bone quality and fracture risk in humans. They further speculate that since circulating homocysteine depends on folate, vitamin B6 and vitamin B12, it may prove suitable as a risk indicator for micronutrient-deficiency-related osteoporosis.

  • Proteins / Casein:
    J-P Bonjour (J Am Coll Nutr (2005): Dietary protein: an essential nutrient for bone health) suggests that low protein intake negatively affects bone health, with deterioration in bone mass, micro architecture and strength, and that protein supplementation as given in the form of casein, attenuates post-fracture bone loss, among other benefits, with relatively high protein intake being associated with increased bone mineral mass and reduced incidence of osteoporotic fractures.

    Osteoporosis Watch Commentary:
    Bonjour draws several corollary conclusions:
    (1) that there is no consistent evidence for superiority of vegetal [vegetable-origin] over animal proteins on calcium metabolism, bone loss prevention and risk reduction of fragility fractures, but we note that this could be presented in reverse, that is, that there is no consistent evidence for superiority of animal proteins over vegetable-origin proteins, and as we know that higher vegetable in take is associated with numerous beneficial effects acrfoss a broad spectrum of potential disease states, something for which there is limited evidence of - or even or evidence to the contrary - with respect to animal proteins, this on its own and in a broader context does not motivate higher animal protein consumption, only higher protein consumption, most prudently more a preponderance of vegetable sources.
    (2) that dietary proteins also enhance IGF-1, a factor that exerts positive activity on skeletal development and bone form. However, as we note on our evidence-based Breast Cancer Prevention Watch site, as well as on Breast cancer Watch, IGF (insulin/insulin-like growth factor, a factor closely related to insulin) interferes with cancer therapy, adversely affecting prognosis, and insulin and IGF-1 are important growth factors, acting through the tyrosine kinase growth factor cascade in enhancing tumor cell proliferation, and indeed the balance of the evidence shows that alteration of glucose metabolism (glucose, insulin, and IGF-1 pattern) is related to breast cancer development and that furthermore there is an association of breast cancer risk in young women with elevated IGF-I (especially among premenopausal women). It is also the case that there appears to be a synergy on breast cancer risk for IGF-I with the hormones estrone or testosterone in both pre and postmenopausal women. See Breast cancer Watch and Breast Cancer Prevention Watch for all supporting studies.

  • HRT:
    Preventing fractures in women with osteoporosis by giving hormone (estrogen) replacement therapy remains controversial, in the wake of WHI and other studies demonstrating a small but significant increase in breast cancer risk modulated by duration of use, as well as a larger risk of VTE (venous thromboembolism). Furthermore, it is also well-established that unopposed estrogen use significantly increases the risk of endometrial cancer (see the Cochrane Review), a risk that is not negated even with long-term use of sequential combined HRT, although the risk is not present under continuous combined estrogen + progestogen regimens.

  • Inhaled Corticosteriods (ICS):
    Although there have been conflicting results concerning the long-term effects of treatment with inhaled corticosteroids (ICS) on bone, a recent study (Pharmacoepidemiol Drug Saf (2004):
    Use of inhaled corticosteroids and bone mineral density in a population based study: the Nord-Trondelag Health Study (the HUNT Study) found an association between ICS and lower BMD.


  • Opiates and Anticonvulsants :
    Certain types of CNS (central nervous system)-active drugs, including benzodiazepines, anticonvulsants, antidepressants, and opioids, have at various times been associated with increased risk of fracture, but it is unclear whether this is related to an effect of bone mineral density or to other factors, such as increased risk of falls (Kinjo et al., Am J Med (2005): Bone mineral density in subjects using central nervous system-active medications) so the researchers examined the relationship between BMD (bone mineral density) and the use of benzodiazepines, anticonvulsants, antidepressants, and opioids, finding that anticonvulsants and opioids (but not benzodiazepines or antidepressants) were associated with significantly reduced bone mineral density.



  • Osteoporosis Watch Warning:
    Bisphosphonates and Jaw Osteonecrosis

    There have been questions raised concerning the renal safety of long-term bisphosphonate use and a recent study of Guarneri et al. (Oncologist (2005): Renal Safety and Efficacy of i.v. Bisphosphonates in Patients with Skeletal Metastases Treated for up to 10 Years) is reassuring: they found that renal function is maintained in patients receiving multiple cytotoxic therapies along with prolonged treatment administration of bisphosphonates; however, there appears to be increased incidence of osteonecrosis of the jaw (ONJ) with prolonged bisphosphonate administration. Bamias et al. (J Clin Oncol (2005): Osteonecrosis of the Jaw in Cancer After Treatment With Bisphosphonates: Incidence and Risk Factors) found that the incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months, with the cumulative hazard significantly higher with zoledronic acid (Zometa) compared with pamidronate (Aredia) alone or pamidronate and zoledronic acid sequentially.

    And Guarneri et al. (cited above) found that jaw osteonecrosis occurred in 5% of the study population, although they correctly note that a causal relationship between bisphosphonate therapy and jaw osteonecrosis has not to date been proven. Previous dental procedures may be a precipitating factor, and it may be prudent that such at-risk patients might also receive appropriate prophylactic attention to maintain oral health, including careful assessment of dental status, and exercising extra precautions when carrying out dental surgery procedures in patients on bisphosphonate therapy, such as strict aseptic techniques, performing atraumatic surgery, and achieving primary wound closure when possible (Guarneri et al., cited above). See Ficara et al., J Clin Periodontol (2005): Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment who also found that jaw osteonecrosis appears to be associated with the intravenous use of bisphosphonates, with all affected patients showing a history of extraction of periodontally hopeless teeth preceding the onset of osteonecrosis, and with duration of bisphosphonate therapy at presentation ranged from 10 to 70 months. But although a large proportion of cases are associated with tooth extractions (approx. 70%), some affected patients have no history of dental manipulation. And Migliorati et al. (Cancer (2005): Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone) confirmed this association, while finding that the most common clinical presentations of osteonecrosis were infection and necrotic bone in the mandible, with associated events included dental extractions, infection, and trauma, although we note that here too two patients are reported to have developed disease spontaneously, without any clinical or radiographic evidence of local pathology. See also Schirmer et al. (Mund Kiefer Gesichtschir (2005): Bisphosphonates and osteonecrosis of the jaw [in German]).

    Furthermore, researchers at the Tel Aviv Sourasky Medical Center (Shlomi et al., Harefuah (2005): Avascular necrosis of the jaw bone after bisphosphonate therapy [in Hebrew]) found that maxillary and mandibular osteonecrotic foci accompanied by pain, inconvenience and purulent exudates in patients who were taking pamidronate, zolendronate or alendronate; affected patients were all treated under the osteomyelitis protocol, with variable esponse to therapy: several weeks to many months, with some cases requiring repeat surgical intervention (curettage or sequestrectomy). Interestingly, the Israeli researchers note that all affected patients also had a recent dental extraction. Typical presenting lesions are either a nonhealing extraction socket or an exposed jawbone, refractory to conservative debridement and antibiotic therapy (Ruggiero et al., J Oral Maxillofac Surg (2004): Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases).

    Osteoporosis Watch notes that prior to these findings, it was thought that the association was restricted to IV-administered bisphosphonates like zoledronic acid and pamidronate, but it now appears that alendronate (Fosamax) exhibits similar adverse potential for maxilliary / mandibular / jaw ostenecrosis. And Osteoporosis Watch has found reports suggesting that the problem may extend to other oral bisphosphonates like risedronate (Actonel): see Carter et al. (Med J Aust (2005): Bisphosphonates and avascular necrosis of the jaw: a possible association), and Purcell & Boyd (Med J Aust (2005): Bisphosphonates and osteonecrosis of the jaw) reporting the records of the Adverse Drug Reactions Advisory Committee (ADRAC) in Australia, involving a total of 129 reported cases, with seven implicating oral alendronate (Fosamax) or risedronate (Actonel).

    Presenting symptoms included localised pain, numbness and altered sensation, exposed bone in the oral cavity, soft tissue infection, loosening of several teeth, and a dental abscess after radiotherapy, with all reports describing the osteonecrosis as occurring in the jaw, four specifically in the mandible, and two in the maxilla. There is currently no wholly effective treatment for the condition, and it is therefore advised (Purcell & Boyd, above) that when intravenous or high-dose oral bisphosphonates are administered, it may be prudent to refer patients for full dental assessment and treatment before the start of therapy and once bisphosphonate therapy has begun, there should be regular clinical monitoring of oral health. They further note that avoiding tooth removal and dental implants, non-surgical control of periodontal disease, and use of soft liners on dentures also seem prudent, and major debridement surgeries should be avoided if at all possible. In established cases of osteonecrosis, the primary goals are palliation and control of osteomyelitis. In most cases, progression can be controlled with long-term or intermittent courses of dicloxacillin or cephalexin for the treatment of any secondary infection, chlorhexidine mouthwash (Peridex, Corsodyl, Savacol), and periodic minor debridement of soft-textured sequestrating bone and wound irrigation.

    And Wooltortan (CMAJ (2005): Patients receiving intravenous bisphosphonates should avoid invasive dental procedures) summarizes the major recommendations in this connection: "Patients who are to receive intravenous bisphosphonates should be warned of this potential effect. If time permits before the drug therapy is initiated, a dental examination may detect and allow treatment of tooth or gum problems that could predispose a patient to osteonecrosis. Proper denture fit should be ensured and good dental hygiene reinforced. The oral hard and soft tissues of patients taking these drugs should be examined every 3 months or so. Invasive procedures that may require bone to heal, such as tooth extractions and bone biopsies, should be avoided if possible. When dental surgery is required, it is uncertain whether cessation of bisphosphonate therapy decreases the risk of necrosis. Prompt referral to a dentist or oral maxillofacial surgeon is recommended for patients with facial symptoms of osteonecrosis, although surgery in the affected area may exacerbate or prolong the condition. Conservative management includes culturing any lesions and using antibiotics as appropriate, and recommending an antiseptic oral rinse that contains chlorhexidine gluconate", although they note that unfortunately, some affected patients may ultimately require the resection of portions of their jaw.

    Note that this side effect had not been detected in the clinical trials carried out prior to marketing of IV-administered bisphosphonates, and it was not until September 2004 when the manufacturer Novartis, confronted with an increasing number of adverse reports and the FDA issued a warning communication and modified the recommendations for use of Zometa and Aredia, including osteonecrosis among the potential side effects (under “Postmarketing experience” and “Precautions for use”), with studies initiated to explore the relationship between bisphosphonate therapy and osteonecrosis (Jimenez-Soriano & Bagan, Med Oral Patol Oral Cir Bucal (2005): Bisphosphonates, as a new cause of drug-induced jaw osteonecrosis: an update (pdf) [in Spanish and English]). Unfortunately, no comparable warning or modification of recommendations has been issued for the oral bisphosphonates that Osteoporosis Watch believes are now also implicated. The FDA also issued a "Dear Dentist Letter" in conjunction with Novartis (Novartis Pharmaceuticals Co (May 5, 2005): Important drug precaution for dental health professionals with patients being treated for cancer [letter to dentists]. Rockville (MD): US Food and Drug Administration [pdf]) recommending that recommends that "cancer patients receive a dental examination prior to initiating therapy with intravenous bisphosphonates (Aredia and Zometa), and avoid invasive dental procedures while receiving bisphosphonate treatment. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition". However, Osteoporosis Watch notes that this warning is in error, as it (1) it is incorrectly narrowly constrained to cancer patients (on the weight of the research we cite above, incidence includes cases outside the oncology sphere), and (2) it is incorrectly narrowly constrained to intravenous bisphosphonates, but on the weight of the research cited above, incidence with oral bisphosphonates is attested, and although to date only with the oral agents alendronate (Fosamax) and risedronate (Actonel), Osteoporosis Watch has no reason to believe that the potential for comparable adverse events does not also apply to other oral bisphosphonates.

    Osteoporosis Watch Practice Guideline
    Therefore, until evidence to the contrary arises, patients should be advised and warned of the potential for all bisphosphonates, both in the normall osteoporotic therapy setting, and in the oncology setting, to lead to jaw osteonecrosis, and that furthermore, all at-risk patients using bisphosphonates receive prophylactic attention for the maintainance of optimal oral health, including regular clinical assessment of dental status and oral health, with observed extra precautions under dental surgery procedures (including but not limited to strict aseptic techniques and atraumatic surgery if feasible, avoidance wherever possible of tooth removal and dental implants and major debridement surgeries, and non-surgical periodontal disease control, antiseptic oral rinse with chlorhexidine-based mouthwash, among other appropriate precautions and interventions. Breast Cancer Watch has investigated this further and notes:
    (1) that penicillin and clindamycin are the mainstay of treatment, yet Zarychanski et al. (above) observed that treatment with an extended course of clindamycin at any rate conferred no clinical benefit, although penicillin (and perhaps also doxycycline) may still be effective; and
    (2) oral rinsing with chlorhexidine (Peridex, Corsodyl, Savacol) even at a relatively low concentration is effective: see Young et al. (Clin Oral Implants Res (2002): The effects of an immediately pre-surgical chlorhexidine oral rinse on the bacterial contaminants of bone debris collected during dental implant surgery) using 0.1% chlorhexidine digluconate mouthrinse. Note that in the case reports of Pastor-Zuazaga et al. (Med Oral Patol Oral Cir Bucal (2006): Osteonecrosis of the jaws and bisphosphonates. Report of three cases [pdf]) the authors used a combination of antibiotic therapy (amoxicilline, clarythromycin, with possible alternative use of penicillin or erythromycin, and both chlorhexidine gel and rinse application, to achieve favorable evolution, with some limited debridgement as needed, providing significant pain relief and at least partial healing. And these researchers, against the customary advice of many others and most major promulgated guidelines, stand in agreement with R Marx (J Oral Maxillofac Surg (2005):Bisphosphonate-Induced Exposed Bone (Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment) and (J Oral Maxillofac Surg (2003): Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic) agree with RE Marx's recommendation of a two months interruption of bisphosphonates. And note that Marx has found that who concluded that effective control to a pain free state without resolution of the exposed bone is 90.1% effective using a regimen of antibiotics along with 0.12% chlorohexidine antiseptic mouth.

    New Clues
    (1) Ardine et al. (Ann Oncol (2006): Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?) who speculate that hypocalcemic coupled with elevated PTH serum levels may be a predisposing factor for ONJ in MBC patients).
    (2) Hansen et al. (J Oral Pathol Med (2006): Osteonecrosis of the jaws in patients treated with bisphosphonates – histomorphologic analysis in comparison with infected osteoradionecrosis) examined the histologic findings of ONJ cases, comparing to that of infected osteoradionecrosis (IORN), finding that in all cases, Actinomyces - a gram positive bacterium and frequently opportunistic pathogen, especially of the oral cavity, and often associated with IUD use - attached to the necrotic bone tissue.
    Indeed, Breast Cancer Watch, noting:

    (1) the consistent association of ONJ and pathogens of the physiological flora of the oral cavity, especially Actinomyces, inducing aggressive infection in the bone, and
    (2) the dramatic relief in symptomology secondary to local and systematic anti-bacterial therapy, with patients often becoming wholly asymptomatic,

    now believes that we can no longer consider bisphoosphonates alone as causative of ONJ, but rather must acknowledge the joint role of oral pathogens in the complex pathogenesis of ONJ. In confirmation of this, Christine Dannemann of the Department of Cranio-Maxillofacial Surgery at the University Hospital of Zurich and her colleagues (Dannemann et al., Swiss Med Wkly (2006): Clinical experiences with bisphosphonate-induced osteochemonecrosis of the jaws [pdf]) who observed that even after successful surgery in some patients, dehiscence of the bone occurred subsequently, but patients became asymptomatic after undergoing anti-bacterial therapy, consisting of both antibiotics and anti-bacterial rinsing, which also suggests a potential role for antibiotic prophylaxis if any invasive dental treatment is necessitated during bisphosphonate therapy.

    Osteoporosis Watch further discovered that two non-prescription agents are also active and effective against various forms of orally resident Actinomyces:
    (i) a baking soda toothpaste (see Zambon et al. (Compend Contin Educ Dent Suppl (1996): A microbiological and clinical study of the safety and efficacy of baking-soda dentifrices) who found that both a dentifrice containing 52% baking soda and 3% sodium percarbonate (Arm & Hammer PeroxiCare) as well as another dentifrice containing 65% baking soda (Arm & Hammer Dental Care) resulted in statistically significant reductions in the levels of Actinomyces species); and
    (ii) the antimicrobial mouth rinse Listerine completely eradicated a broad spectrum of oral microorganisms in 10 to 30 seconds, including Actinomyces viscosus (as well as methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, and even Candida albicans, among many others), and may even be effective in providing some significant analgesia, probably the investigators speculated, due to a decrease in oral bacteria by the antimicrobial action of Listerine, leading to lowering the inflammatory response of the host (Okuda et al., Bull Tokyo Dent Coll (1998): The efficacy of antimicrobial mouth rinses in oral health care).

    Osteoporosis Watch also observes that to date all instances of ONJ have been associated with third generation nitrogen-containing bisphosphonates (such as pamidronate (Aredia), zoledronic acid (Zometa), ibandronate (Boniva), alendronate, risedronate (Actonel)), with no documented incidence of ONJ associated with non-nitrogen-containing bisphosphonates (no nitrogen ring) such as clodronate (Bonefos) and etidronate (Didronel).

    Osteoporosis Watch further notes that etidronate is effective only in vertebral, but not in nonvertebral bone activity and fracture, which to our mind both severely limits and deprecates its value as a non-ONJ-promoting bisphosphonate, in contrast to clodronate with activity in both vertebral and nonvertebral domains. Therefore, one viable alternative to the ONJ-promoting bisphosphonates that effectively obviates the issue is deployment of clodronate (Bonefos), although clodronate is to date only available in Canada and Europe.


Osteoporosis - New Frontiers


  • Zoledronic Acid (Zometa):
    Zolendronic acid is a new potent bisphosphonate. In a NEJM study, it was found that infusions of 0.25 mg, 0.5 mg or 1 mg every three months, 2 mg every six months, or 4 mg every 12 months were equally efficacious as oral bisphosphonates on bone density, suggesting that a single zoledronate annual infusion may be an effective and well-tolerated treatment for postmenopausal osteoporosis. However, no significant fracture data has been reported on zoledronic acid, although two fracture trials, HORIZON-PFT and Horizon-RFT are currently underway with planned completion around 2005. Zoledronic acid, FDA-approved for bone metastasis, is not currently approved for osteoporosis treatment. (Recent studies suggest that zoledronic acid is more effective than pamidronate, another bisphosphonate, in bone metastasis therapy in breast cancer (see the recent study in Cancer)). There are some case reports of zoledronic acid associated hypocalcaemia (see Reactions: Pamidronic acid/zoledronic acid: Hypocalcaemia.

  • Osteoporosis Watch Commentary:
    Despite the appeal of a once yearly regimen, there are no studies to date to determine how long after the year bone turnover suppression induced by zolendronic acid may last. Furthermore, the long-term effects of extreme bone turnover suppression, as exhibited by zolendronic acid, are undetermined and may not ultimately be benign.

  • Pamidronate (Aredia):
    Pamidronate, a new potent bisphosphonate, currently approved for the treatment of Paget's disease, hypercalcemia of malignancy, multiple myeloma, and bone metastases from solid tumors, is sometimes used "off-label" to treat osteoporosis in patients who are not able to tolerate oral bisphosphonates, in a regimen of initial 90 mg intravenously, then 30 mg intravenously every 3 months, typically infused over 1 hour. Although used for the treatment of bone metastasis in breast cancer, recent studies suggest it is not as effective as zoledronic acid for such therapy (see the recent study in Cancer).

    For pamidronate, published data are insufficient to fully conclude efficacy, and minimal fracture rate data has been reported for pamidronate in the treatment of osteoporosis to date. However, the recent work of Sumnik et al with children (Horm Res: Effect of Pamidronate Treatment on Vertebral Deformity in Children with Primary Osteoporosis) does suggest that pamidronate significantly benefits restoration of vertebral fractures in this population with primary osteoporosis. And it should be noted that an unpublished report by R. Nord and J. Lane at the Hospital for Special Surgery has demonstrated comparable benefit for intravenous pamidronate and oral alendronate in terms of fracture reduction (see the HSS Special Report:
    Intravenous Bisphosphonate Treatment for Osteoporosis).

    In addition, there is some interest in the analgesic effects of parenteral bisphosphonates like pamidronate. Thus, 60 mg of pamidronate infused every 3 months for 1 year to patients with osteoporotic vertebral fractures improved pain relief after only 3 months of treatment for both patients with primary osteoporosis and with glucocorticoid-induced osteoporosis (see the recent Medscape review on Optimizing Bisphosphonate Therapy in Osteoporosis).

    Pamidronate has been associated with some severe skin reactions, euveitis, scleritis, episcleritis, and conjunctivitis, although these appear relatively rare, and reversible with discontinuation of therapy. In addition, there have been some few cases of reversible pamidronate-induced nephrotoxicity: see most recently Clin Nephrol: Pamidronate-induced Nephrotoxic Tubular Necrosis – A Case Report as well as hypocalcaemia (see Reactions: Pamidronic acid/zoledronic acid: Hypocalcaemia. (Note that the oral form of pamidronate has been associated with a high incidence of esophageal complications and consequently is no longer marketed in North America for osteoporosis treatment.)

  • Ibandronate (Boniva):
    Ibandronate, a new potent bisphosphonate, has been shown to increase BMD in a dose-dependent manner with a corresponding decrease in biochemical markers of bone resorption. (It has also been used to treat hypercalcemia of malignancy at doses of 0.2 to 6 mg).

    Ibandronate has been studied for quarterly IV use (see the ARD study), and it appears that quarterly IV ibandronate may be an effective alternative to oral bisphosphonates and HRT for bone loss prevention in postmenopausal women.

    A daily oral formulation of ibandronate has only been recently (March 2005) approved in the United States (as Boniva, from Roche / GlaxoSmithKline). The lowest effective oral dose is 2.5 mg daily, and at this dose no significant increase in side effects over placebo were seen. Furthermore, the increase in bone mass and decrease in biochemical markers of bone resorption was comparable to that seen with alendronate at 10 mg daily. Indeed, Felsenberg et al. reporting on the BONE (Ibandronate Osteoporosis Vertebral Fracture trial in North America and Europe) study outcomes (Bone (2005): Oral ibandronate significantly reduces the risk of vertebral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis) found that in addition its efficacy in significantly reducing the risk of new vertebral fractures of all severities, oral daily ibandronate also has a pronounced effect on the more severe most clinically relevant vertebral fractures, with a significant and sustained reduction of 59% in the relative risk of combined new moderate and severe vertebral fractures observed over three years.

    Ibandronate has also been studied for weekly oral use at 20mg once-weekly (see the NCEM study and the JIM study), these studies demonstrating that oral weekly ibandronate exhibits the same efficacy and safety as oral daily ibandronate for postmenopausal women with osteoporosis, with significant and sustained anti-fracture efficacy (this latter point settles earlier questions concerning whether ibandronate reduces risk of fractures). See also the recent review of Barrett et al. (J Clin Pharmacol:
    Ibandronate: a clinical pharmacological and pharmacokinetic update)

    In addition, oral intermittent regimens appear to be equi-efficacious: Delmas et al. (Osteoporos Int (2004):
    Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study) presented results from the BONE study evaluating oral ibandronate administered daily (2.5 mg/day) or intermittently (20 mg every other day for 12 doses every 3 months, finding both regimens normalized the rate of bone turnover, provided significant increases in BMD and a marked reduction in the incidence of vertebral fractures. Furthermore, this was further confirmed and refined by Chesnut et al. (J Bone Miner Res (2004): Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis) which is the first time that significant fracture efficacy has been prospectively shown with an intermittently administered bisphosphonate in a randomized, controlled (RCT) clinical trial; note that the study found a significant relative risk reduction in clinical vertebral fractures on both daily and intermittent ibandronate regimens, although only the daily regimen reduced the risk of nonvertebral fractures in a higher-risk subgroup (femoral neck); similar findings are reported by P. Miller (Clin Ther (2005): Optimizing the management of postmenopausal osteoporosis with bisphosphonates: the emerging role of intermittent therapy). And after 1 year of therapy, patients who received ibandronate 150 mg once monthly had a significantly greater increase from baseline in lumbar spine BMD than those who received ibandronate 2.5 mg/d , with similar overall adverse-event profiles patients on the monthly schedule reported more flulike symptoms (Pyon, Clin Ther (2006): Once-monthly Ibandronate for postmenopausal Osteoporosis: Review of a new dosing regimen).


    Side effects were uncommon, and ibandronate was well-tolerated (at these doses side effects included hyperthermia, hypocalcemia, and hypophosphatemia, as well as flu-like symptoms and GI disturbances).

    MOBILE Study Results:
    Roche / GlaxoSmithKline (GSK) have announced (Miller et al., J Bone Miner Res (2005): Monthly Oral Ibandronate Therapy in Postmenopausal Osteoporosis: 1-Year Results From the MOBILE Study) results of the one year endpoint of their ongoing two year MOBILE (Monthly Oral Ibandronate in Ladies) trial, a phase III multinational RCT examining the viability of a more convenient once-monthly oral ibandronate therapy for post menopausal osteoporosis. MOBILE is comparing the efficacy and safety of the oral daily ibandronate (already FDA approved) regimen with three alternate monthly regimens: (1) 100 mg on a single day, (2) 100 mg, delivered as separate 50 mg doses on two consecutive days; and (3) 150 mg on a single day. The one year findings establish that all three monthly regimens were equivalent to the 2.5 mg daily regimen in increasing lumbar spine Bone Mineral Density (BMD).

    In addition, these recent findings now include anti-fracture efficacy data, showing that oral ibandronate, whether given daily (2.5 mg) or intermittently (dosing free interval > 2 months), significantly reduces 3-year vertebral fracture risk by 52% and 50%, respectively; and once monthly dosing has been found to achieve comparable benefits (Reginster et al, Osteoporos Int (2005): A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate)

    In summary, as Bauss and Russell conlude in a recent review (Osteoporos Int:
    Ibandronate in Osteoporosis: Preclinical Data and Rationale for Intermittent Dosing) "ibandronate is the only bisphosphonate so far proven to reduce the risk of vertebral fractures significantly with a between-dose interval >2 months, in a prospective clinical trial", further noting the existing evidence on ibandronate illustrates "that the total cumulative dose of bisphosphonate administered determines the response, independent of whether the dose is given daily or less frequently in a given time period".

    Direct and robust evidence of a reduction in the risk of fractures has been demonstrated with an intermittent ibandronate regimen. The BONE trial (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) - see the summary by Demas et al:
    Antifracture Efficacy of Oral Ibandronate given with a Between-dose Interval of >2 Months in Postmenopausal Osteoporosis) - studied the efficacy and safety of oral ibandronate administered daily or with a between-dose interval greater than two months (20mg every other day for 12 doses every three months), finding that the intermittent regimen demonstrated an anti-fracture efficacy equivalent to the oral daily regimen.

    Alternative intermittent IV injection regimens are being further investigated in the onging DIVA (dosing IV administration) trial, comparing the efficacy and safety of two IV dosing regimens (2mg every two months and 3mg every three months) compared with oral daily ibandronate, and the recent Admai et al. study (Bone:
    Efficacy and safety of ibandronate given by intravenous injection once every 3 months) has already confirmed safety and efficacy of a 2 mg. intravenous injection of ibandronate in a once per 3 months regimen.

  • Strontium Ranelate (SR)

  • Commercial Availability Update:
    Strontium ranelate, as PROTELOS from Servier Laboratories, received on September 21, 2004 marketing authorization across 27 European countries, including the UK. PROTELOS is now available in the UK for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures.

    Strontium Ranelate: Current Status in Osteoporosis Therapy
    Strontium ranelate (SR), a trace earth element, is currently being developed as a novel osteoporosis therapy. Pharmacologic studies suggest that SR optimizes bone metabolism by decreasing bone resorption and promoting bone formation (given that these dual modes, strontium ranelate does not appear to be a purely anabolic agent). It's efficacy in osteoporosis therapy is now well-established and to date it exhibits no appreciable adverse effects (see the review of Reginster et al, Expert Opin Investig Drugs (2004):
    Strontium ranelate: a new paradigm in the treatment of osteoporosis). Furthermore,earlier results of the TROPOS as well as a 3-year analysis of the SOTI study and study demonstrate its efficacy in the reduction of non-vertebral, including hip, as well as vertebral, fractures (Delmas, Osteoporos Int (2004): Clinical effects of strontium ranelate in women with postmenopausal osteoporosis).

    Maunier et al. (New Engl J Med (2004):
    The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis) observe that strontium ranelate dissociates bone remodeling by increasing bone formation and decreasing bone resorption, and find that its use is associated with early and sustained reductions in the risk of vertebral fractures along with increase in BMD,, with no significant differences between the treatment and control (placebo) groups interms of incidence of serious adverse events.

    Three phase III trials are currently underway (the FIRST trial, SOTI assessing vertebral fracture risk, and TROPOS, assessing peripheral (non spinal) fractures; early findings demonstrate impressive efficacy in the reduction of both vertebral and peripheral fractures, coupled with the striking fact that SR does not induce any significant adverse reactions compared to the placebo group. And another NEJM-reported recent phase III trial: The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis has concluded that strontium ranelateeffects early and sustained reductions in the risk of vertebral fractures with no above-placebo level adverse events.

    Two additional trials, PREVOS and STRATOS have returned important contributuions to knowledge of optimal SR regimens. The PREVOS study (PREVention Of early postmenopausal bone loss by Strontium ranelate) determined the minimum effective SR dose in bone loss prevention in early postmenopausal nonosteoporotic women to be 1mg SR, while the STRATOS study (STRontium Administration for Treatment of OSteoporosis) determined the dose to be 2mg SR in the treatment of postmenopausal osteoporosis.


  • Tibolone:
    [updated 03/14/07]




  • LIFT Tibolone Study Halted: Increased Risk of Stroke
    Evidencewatch reports an early termination of the Organon LIFT study investigating tibolone efficacy on new vertebral fractures in elderly osteoporotic women under DSMB and Steering Committee rules. The interim findings reported an increased incidence of ischemic plus hemorrhagic events (strokes) in tibolone treatment group compared to the control group.

    The precise and full clinical implications however are not wholly clear:


    1. The study population was elderly osteoporotic women with a high risk of fracture, with the average age at baseline (study entry - recruitment began in 2001, and recruitment completed June 2003) of 68. Yet the vast majority of tibolone users average 10 years younger given typical deployment for vasomotor (climacteric) hot flashes. Indeed, Osteoporosis Watch notes that Organon scientists determined in 2004 that at least in the UK, tibolone was preferentially prescribed to women with an increased risk for breast and endometrial cancer (Wierik et al. Climacteric (2004): Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study).

    2. The Organon Tibolone Clinical Study Database, comprised of more than 6500 women-years of tibolone use in women who are on average much younger than the elderly osteoporotic women included in the LIFT study, fails to suggest any significant increased risk of stroke.

    3. The study dose used in the LIFT study was 1.25 mg./daily, and indeed 1.25 mg also (as compared with 2.5 mg/daily) significantly decreases hot flashes, although the higher 2.5 mg tibolone dose is both faster in onset of action and with higher reductions in hot flash frequency and severity. However, it is important to note that the clinical trial database does not suggest that in younger postmenopausal women treated with either dose of tibolone, 2.5 mg nor 1.25 mg, there is any increased risk on stroke.

    4. It appears that the parameter with the most impact in the LIFT study's outcome regarding stroke is age, although this is also true for the placebo group. The fact that NO increases in incidence of VTE (venous thromboembolism) nor MI (myocardial infarction) are found with tibolone makes it more difficult to explain the mechanism by which tibolone increases the risk on stroke in these elderly women (I am indebted to Dr. Mirjam Mol-Arts, Livial Global Venture Teamleader and head of clinical projects in HRT at Organon, manufacturer of tibolone (Livial), for this clarification).

      Indeed,
      Osteoporosis Watch notes that in our own research, some studies have found tibolone (2.5 mg/daily) to be safe in postmenopausal patients with high risk factors in their history such as thromboembolic disorders, diabetes mellitus, hypertension, cardiovascular disease, pulmonary embolism, and stroke (see F. Szanto, Tibolone therapy in postmenopausal women with a history of many risk factors) over a 36-month period, a finding hard to reconcile with the LIFT results.

    5. Against the thrust of the LIFT study findings on stroke, tibolone as a six-month course (at 2.5 mg/daily) in postmenopausal women was found to counteract the increase of the intima media thickness (IMT) of the common carotid arteries (CCA), as determined by Anedda et al. (Hormone Res (2004): Observational Study on the Efficacy of Tibolone in Counteracting Early Carotid Atherosclerotic Lesions in Postmenopausal Women) and also by Erenus et al. (Fertil Steril (2002): Effect of tibolone treatment on intima-media thickness and the resistive indices of the carotid arteries), and this suggests an anti-atherosclerotic effect by tibolone, as it is well-established that increased CCA-IMT values are associated with a higher risk of long-term stroke recurrence (Tsivgoulis et al., Stroke (2006): Common Carotid Artery Intima-Media Thickness and the Risk of Stroke Recurrence). [Tibolone's effect on CRP (C-reactive protein), also a risk factor for stroke, is not wholly clear, as there have been inconsistent findings across studies.]


§ Some Guidance on Stroke Risk Reduction

Osteoporosis Watch continues to investigate this issue and will post additional guidance as appropriate, but pending that advises that women currently using tibolone explore this matter candidly with their physicians. Osteoporosis Watch advises, however, for any women who elects to continue tibolone therapy that at the very least some basic proactive stroke-preventive measures be taken:


  • Tibolone is a new class of agent known as a STEAR (Selective Tissue Estrogenic Receptor Regulator), and appears to be exceptionally promising for the relief of menopausal symptoms, among several other beneficial actions. L. Speroff and TB Clarkson (Contemporary Ob/Gyn: Is tibolone a viable alternative to HT?) reviewed the literature and affirm the viability of tibolone ((derived from soybeans and yams, and already well-established for its ability to prevent bone loss) as an alternative to HRT, and this landmark report furthermore found tibolone as effective as HRT in the relief of hot flashes and vaginal dryness, while significantly improving sexual response, all with an excellent side effect profile. Furthermore, tibolone exhibits several additional beneficial activities. It lowers estrogen breast tissue concentration, with no cell-proliferative activity, potentially protective in breast cancer; the ongoing LIBERATE (Livial Intervention following Breast cancer Efficacy, Recurrence And Tolerability Endpoints) trial seeks to clarify this further, by studying menopausal symptom relief in postmenopausal women with a history of breast cancer, where traditional hormone therapies (estrogen / progesterone) are contraindicated, leaving these women without any approved treatment option for relief of menopausal symptoms like hot flashes and night sweats. (Other confirming studies have recently appeared, among them Langren et al. (Maturitas (2004): Tibolone relieves climacteric symptoms in highly symptomatic women with at least seven hot flushes and sweats per day).

    Note that some reseachers identify tibolone more precisely as within a new class of SEEMs: Selective Estrogen Enzyme Modulators, agents showing an inhibitory effect on sulfatase and 17-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase and consequently on the levels of tissular levels of estradiol; that is, within a class of agents with a constellation of breast cancer-protective mechanisms. Osteoporosis Watch views this categorization as more clinically appropriate than the broader STEAR (Selective Tissue Estrogenic Receptor Regulator) designation.

    It has also been shown to be at least as effective as HRT in both the prevention of bone loss and the relief of menopausal symptoms, even out to 8 years (see Prelevic at al. (Maturitas:
    The Effect of Tibolone on Bone Mineral Density in Postmenopausal Women with Osteopenia or Osteoporosis -- 8 Years Follow-Up) and thus is a viable and safe HRT alternative (on menopausal symptom relief; see also Riera-Espinoza et al. (Maturitas: Changes in bone turnover during tibolone treatment). Also consult the Osteoporosis Watch coverage on Menopause).

    The LIFT (Long-term Interventional Fracture Study in Osteoporotic Patients) trial (in the Nettherlands), as well as trials at USCD and Rush-Presbyterian-St. Luke’s Medical Center (Chicago,) among others, are assessing tibolone's effect on fracture risk reduction. One intriguing recent finding is that tibolone may, in addition to its benefits for menopausal symptoms and bone health, counteract carotid atherosclerotic lesions as well as induce reductions in Lpa (lipoprotein(a)), total-cholesterol, and LDL-C (LDL-cholesterol) in postmenopausal women; see Anedda et al. (Hormone Research:
    Observational Study on the Efficacy of Tibolone in Counteracting Early Carotid Atherosclerotic Lesions in Postmenopausal Women).

    Osteoporosis Watch Commentary:
    In a recent comprehensive review of tibolone in Contemporary OB/GYN, the authors examine the issue of endometrial effects and conclude: "We can state with confidence that tibolone does not cause endometrial proliferation" although the authors acknowledge that isolated cases of endometrial proliferation have been reported. However, one just released study ( Perez-Medina et al.:
    Tibolone and Risk of Endometrial Polyps: A Prospective, Comparative Study with Hormone Therapy) in NAMS Menopause, has found that tibolone significantly increased the risk of endometrial polyps. The import of this seemingly contrary finding is not clear at present, and Osteoporosis Watch speculates that it may have been dose-dependent, as the study use 2.5mg/daily of tibolone (typical for menopausal symptom relief), although 1.25mg/daily is an alternate deployable regimen known to still have favorable anti-osteoporotic benefit. We await the results of further studies and trials to clarify this issue, especialy the forthcoming results of the THEBES (Tibolone Histology of the Endometrium and Breast Endpoints Study) trial. See our full discussion of this issue on Menopause Watch.





  • (new) Tibolone and Breast Cancer: Breast Cancer Watch Findings
    As we have noted above, tibolone exerts estrogenic activity on brain, vagina and bone without stimulation of breast and endometrium, and given that this selective activity depends on the specific tissue context, it has been cutomarily classified as a selective tissue estrogenic activity regulator (SERM). As to the breast, tibolone and its metabolites stimulate the formation of inactive estradiol sulfate and estrone sulfate by activation of sulfotransferase, and inhibition of sulfatase. To date, breast safety studies have shown that tibolone inhibits the growth of tumors in a DMBA model, while in breast cell lines, tibolone inhibits sulphatase activity, increases apoptosis and decrease cell proliferation (Kloosterboaer, J Steroid Biochem Mol Biol (2001): Tibolone: a steroid with a tissue-specific mode of action), and its pro-apoptotic effects appear at least partially mediated by a decreased expression of the anti-apoptotic proteins bcl-2 and bcl-xL (Anne Gompel et al., Fertil Steril (2002): In vitro studies of tibolone in breast cells).

    The evidence base shows that in breast tissue tibolone reduces bioactive estrogen tissue levels, as well as in human breast cancer cells (Morris Notelovitz, Medscape General Medicine, 9(1):2 (2007): Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice, and JR Pasquualini & GS Chetrite, J Steroid Biochem Mol Biol (1999): Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications, who concluded in this study that tibolone inhibits local sulfatase activity within the breast and may thereby reduce the formation of biologically active estrogenic compounds), via these major pathways:

    (1) inhibition of the sulfatase conversion of estrone sulfate to estrone(Peter JG van de Ven at the University Medical Center Utrecht, and colleagues, J Steroid Biochem Mol Biol (2002): Effect of tibolone (Org OD14) and its metabolites on aromatase and estrone sulfatase activity in human breast adipose stromal cells and in MCF-7 and T47D breast cancer cells who concluded in this study that because tibolone and its metabolites inhibit sulfatase activity, and because tibolone only increases aromatase activity at high concentrations, the effects of tibolone on the breast are probably safe);

    (2) the reduction of 17beta-HSD type 1 mediated metabolism of estrone to estradiol, where it should be note that 17beta-HSD type 1 oxidizes estradiol to the less active estrone, and to inactive estrone sulfate via estrone sulfotransferase (see (van de Ven et al., above);

    (3) the stimulation of sulfotransferase, which reverses the conversion of estrone sulfate to estrone (Gérard Chetrite and colleagues at the Institut de Puériculture, Anticancer Res (1999): Effect of Org OD14 (LIVIAL) and its metabolites on human estrogen sulphotransferase activity in the hormone-dependent MCF-7 and T-47D, and the hormone-independent MDA-MB-231, breast cancer cell lines, who concluded in this study that the stimulatory effect provoked at low doses by tibolone and its metabolites on the estrogen sulphotransferase which is involved in the biosynthesis of inactive estrogen sulphates in estrogen-dependent breast cancer cells, can contribute to the protection of breast tissue in postmenopausal women with hormone replacement therapy) - and furthermore, tibolone and its delta4-isomer upregulates 17beta-HSD type 2 activity and the conversion of estradiol back to estrone;

    and this tibolone-induced sulfatase activity decrease being tissue specific, with most (70%-90%) occuring in breast cancer cells, but none in osteoblast cells (Marcel de Gooyer, Mol Cell Endocrinol (2001): Tibolone: a compound with tissue specific inhibitory effects on sulfatase who concluded in this study that the tissue specific inhibition pattern of sulfatase activity by tibolone and its metabolites suggest tibolone as protective against the development of mammary carcinomas, while retaining favorable estrogenic effects on bone). Furthermore, tibolone has minimal influence on breast cell proliferation, and shows in addition minimal (2%-6%) increase in post therapy mammographic density (Eva Lundstrom and colleagues at the Karolinska Hospital, Sweden, Am J Obstet Gynecol (2002): Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density who concluded in this prospective randomized study that, in contrast to estrogen/progestogen treatment, tibolone exerted little stimulation of breast tissue, and that treatment with tibolone did not differ from that with placebo).

    In addition, tibolone and its 3ß-OH metabolite demonstrate an anti-invasive effect on MCF-7/6 and T47-D breast cancer cell lines in vitro, with this anti-invasive activity is being correlated with a decreased release of pro-MMP-9 in the medium, and with any effect on cell–cell adhesion or motility (BW Vanhoecke et al, Maturitas (2006): Tibolone and its metabolites inhibit invasion of human mammary carcinoma cells in vitro), nor it would appear with any effect on angiogeneis (FE Frankeene et al., J Clin Oncol (2006): Effect of tibolone on tumor angiogenesis parameters in short-term treated women), and Bindumalini Raobaikady and colleagues (Steroids (2006): Lack of aromatisation of the 3-keto-4-ene metabolite of tibolone to an estrogenic derivative) had previously found that the 7a-methyl norethisterone metabolite of tibolone does not undergo aromatisation to an estrogenic derivative (ethinylestradiol).

    Finally, in their recent small retrospective study, Michalis Goutzioulis and colleagues at the Aristotle University of Thessaloniki (J Obstet Gunaecol Res (2007): Tibolone therapy in breast cancer survivors: A retrospective study) investigated the relationship between tibolone therapy and recurrence or mortality in breast cancer survivors, it appears that tibolone is not associated with a negative impact on breast cancer outcome when given to breast cancer survivors for relief of menopausal symptoms (mean duration of use 37.1 months).

    Our Conclusions on the Safety of Tibolone in Breast Cancer
    From these above-cited studies, Breast Cancer Watch concludes that the weight of the evidence supports the lack of adverse impact, breast-estrogenic or otherwise, of tibolone on breast cancer initiation or progression, and supports breast anti-estrogenic, anti-proliferative, pro-apoptopic,and anti-invasive activity, and hence in its overal effect, is protective against the development of breast carcinomas, while retaining powerful beneficial effects on vasomotor symptomology and bone health.


  • Other Emeging Developments:
    (1)
    Lasofoxifene (Oporia, from Pfizer) is a new potent SERM in phase 3 trials which at low doses decreases bone loss, reduces serum cholesterol, and exhibits an antiproliferative effect on breast cells with no uterine hypertrophy activity; a worldwide trial, PEARL, targeted for completion in 2006, will clarify other issues of efficacy and safety. However, in September 2005, the FDA rejected Pfizer submitted NDA for Oporia (lasofoxifene) as a preventative therapy for osteoporosis.

    (2) Similarly, Bazedoxifene (Wyeth) is also under phase 3 trials as a SERM anti-osteoporotic.

    (3) AMG-162 (Amgen), a humanized monoclonal antibody in the class of OPGs (osteoprotegrin), is being studied as an extended-effect antiresorptive agent, delivering beneficial bone activity over a six-month duration from a single injection.

    (4) NO-flurbiprofen (also known as HCT 1026, from NicOx) under early trials operates within the class of NO-releasing (nitric oxide) NSAID derivatives and exhibits both antiresorptive and potent analgesic activity with few adverse effects.

    (5) Tofupill/Femarelle (also known as DT56a) is novel soy-based phyto-selective SERM, studied at the Sheba Medical Center in Israel, which increases BMD in postmenopausal women, in addition to relieving menopausal symptoms such as hot flashes, without adverse estrogenic effect, as reported recently by Yoles et al (Menopause (2003): Tofupill/Femarelle (DT56a): a new phyto-selective estrogen receptor modulator-like substance for the treatment of postmenopausal bone loss). In a followup study by the same researchers (Yoles et al., Clin Exp Obstet Gynecol (2004):
    Efficacy and safety of standard versus low-dose Femarelle (DT56a) for the treatment of menopausal symptoms) found that the standard dosage of 644 mg/day of Femarelle to benefit both menopausal symptoms and osteoporosis, without affecting endometrial thickness.

    (6) Phytoestrogens: there is some evidence that phytoestrogens (primarily soy protein derivatives in the isoflavanoid class) and certain synthetic soy isoflavones exert some positive effects of BMD and bone markers, although efficacy appears to be tightly bound to product/formulation choices (see the recent comprehensive review in Endocrinol Metab Clin North Am:
    Phytoestrogens—Mechanism of Action and Effect on Bone Markers and BMD; see also the review of Dodin et al in Med Sci (Paris): Phytoestrogens in Menopausal Women: A Review of Recent Findings, and Cotter and Cashman in Nutr Rev: Genistein Appears to Prevent Early Postmenopausal Bone Loss as Effectively as Hormone Replacement Therapy). Note also, that Lydeking–Olsen et al. (Eur J Nutr (2004): Soymilk or progesterone for prevention of bone loss: A 2 year randomized, placebo–controlled trial) found daily intake of two glasses of soymilk (76 mg isoflavones) prevents lumbar spine bone loss in postmenopausal women (but that a transdermal progesterone preparation demonstrating bone–sparing effects combined with soy milk yielded a negative interaction between the two treatments resulting in bone loss to a greater extent than either treatment alone). Similar positive findings have been reported by Haghighian Roudsari et al. (Nutr J (2005): Assessment of soy phytoestrogens' effects on bone turnover indicators in menopausal women with osteopenia in Iran: a before and after clinical trial) who found that 35g soy protein per day for 12 weeks may delay the bone resorption process.

    Osteoporosis Watch however finds the evidence for a positive effect of isoflavones on bone health not wholly conclusive to date. Whereas the double-blind study of Gallagher et al. (Menopause (2004): The effect of soy protein isolate on bone metabolism) did not find a significant positive effect of soy protein isolate supplemented with varying amounts of isoflavones on BMD or on the serum lipid profile in early postmenopausal women, Atkinson et al. (Am J Clin Nutr (2004):
    The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial) did find that loss of lumbar spine bone mineral content and bone mineral density was significantly lower in the women taking the isoflavone supplement, red clover (Promensil) than in those taking the placebo, and although there were no significant treatment effects on hip bone mineral content or bone mineral density, markers of bone resorption, or body composition, yet bone formation markers were significantly increased in the intervention group compared with placebo in postmenopausal women, suggesting that isoflavones have a potentially protective effect on the lumbar spine in wome through attenuation of bone loss.

    In addition, Chen et al. writing in the same journal as that of the Gallagher study (Menopause (2004) :
    Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: a double-blind, randomized, controlled trial) found a modulated beneficial effect on bone mineral content (BMC). However this study may suggest an explanation for the perceived divergence of results: they found that the independent effect of soy on the maintenance of hip BMC is more marked in women in later menopause and in those with lower BW (body weight) or calcium intake, so that the partially determinative factors may be years since menopause (YSM), body weight (BW), and dietary calcium intake for postmenopausal women, factors not explicitly controlled in other studies.

    We speculate that it may be that at least some of the conflicting evdience regarding phytoestrogens and osteoporosis may be due to the differential effect of phytoestrogens on menopausal women taking HRT, versus those not taking HRT: see Arjmandi et al. (J Clin Endocrinol Metab (2003):
    Soy Protein Has a Greater Effect on Bone in Postmenopausal Women Not on Hormone Replacement Therapy, as Evidenced by Reducing Bone Resorption and Urinary Calcium Excretion), who conclude that daily intake of approximately 88mg isoflavones in conjunction with 40g soy protein for 6 months increased bone mineral density and bone mineral content in perimenopausal and postmenopausal women who were not on HRT, but not in those on hormone therapy.

  • Osteoporosis Watch Commentary:
    One synthetic phytoestrogen, ipriflavone, is widely used, especially outside the U.S. as putative natural anti-osteoporotic therapy, based partially on epidemiologic studies and some early reported trial results, however no methodologically sound studies have demonstrated a consistent and convincing benefit. Furthermore, the largest study (Alexandersen et al., JAMA (2005): Ipriflavone in the Treatment of Postmenopausal Osteoporosis) failed to confirm positive effects on BMD and vertebral fractures, but did find a significant incidence of lymphocytopenia (decreased immune lymphocyte concentrations) under ipriflavone treatment, which may in the long-term predispose to opportunistic infections, among other adverse events, although this has not been evidenced in the short-terms studies to date (on this see also the disjunction against ipriflavone use in the 2002 CMA's (Brown et al., CMAJ (2002): Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada as well as the above-cited Endocrinol Metab Clin North Am: Phytoestrogens—Mechanism of Action and Effect on Bone Markers and BMD). Therefore, given unproven efficacy and potential safety issues (especially for patients with immune deficiencies), Osteoporosis Watch does not presently recommend ipriflavone supplementation for osteoporosis treatment, and we await the findings of further trials to ultimately decide its status as a potential osteoporotic.

    (7) Dietary Silicon:
    Burns et al. (Br J Nutr (2003):
    UK Food Standards Agency Optimal Nutrition Status Workshop: environmental factors that affect bone health throughout life) found that there is some evidence to suggest a role for silicon in bone health, in part through regulation of osteoblast function and osteocalcin synthesis. More recently a cross-sectional, population-based study found that dietary silicon (approx. 30 mg/day) correlated positively and significantly with BMD at all hip sites for men and premenopausal women, but not postmenopausal women, and although further studies are call for, this suggests that in these populations increased cortical BMD is benefited by increased silicon intake (see Jugdaohsingh et al., J Bone Miner Res (2004): Dietary Silicon Intake Is Positively Associated With Bone Mineral Density in Men and Premenopausal Women).

    (8) Exercise: Kemler et al. (Arch Intern Med (2004):
    Benefits of 2 Years of Intense Exercise on Bone Density, Physical Fitness, and Blood Lipids in Early Postmenopausal Osteopenic Women: Results of the Erlangen Fitness Osteoporosis Prevention Study (EFOPS)) determined that intense exercise programs with special emphasis on bone density can significantly reduce bone loss and back pain,as well as reduce lipid levels in osteopenic women in early postmenopausal years. In addition, Yamazaki et al. (J Bone Miner Metab: Effect of walking exercise on bone metabolism in postmenopausal women with osteopenia/osteoporosis) found a positive response of lumbar BMD to moderate walking exercise in postmenopausal women with osteopenia/osteoporosis, due to the suppression of bone turnover (and it appears that an early change in the urinary NTX level may be useful to predict the long-term response of increasing lumbar BMD to exercise). Furthermore, Chan et al. (Arch Phys Med Rehabil: A randomized, prospective study of the effects of Tai Chi Chun exercise on bone mineral density in postmenopausal women) found that a programmed TCC (Tai Chi Chun) exercise intervention retarded bone loss in weight-bearing bones for early postmenopausal women.

    (9) Vasodilators/Beta-Blockers:
    Schlienger et al. (JAMA (2004):
    Use of -Blockers and Risk of Fractures) have recently examined whether the beta -blocker propranolol increases bone formation, finding that current use of beta-blockers, taken alone as well as in combination with thiazide diuretics, is associated with a reduced risk of fractures, although the limitations of case-control methodology disallow deducing the precise clinical value of these results. In a related development, Jamal et al. (J Bone Miner Res (2004): Isosorbide Mononitrate Increases Bone Formation and Decreases Bone Resorption in Postmenopausal Women: A Randomized Trial) examined the effect of administering 20 mg. once daily isosorbide on bone turnover in postmenopausal women, finding that isosorbide significantly decreases bone resorption while increasing bone formation. The authors correctly note that in a large trial strontium ranelate is the only other agent currently available that has shown both increases in bone formation and decreases in resorption. Headaches were about four times more common among women on isosorbide compared tothose on placebo and hence this may limit the use of this type of nitrate in the postmenopausal osteoporosis treatment.


    (10) Adverse Effects of Low-dose Prednsione:
    New findings suggest that even low doses of prednisone (5 mg per day) can suppress several bone formation indices in postmenopausal women and may reduce bone repair / renewal, with potentially adverse effects on bone mass and/or bone strength (Ton et al., J Bone Miner Res (2005): Effects of Low-Dose Prednisone on Bone Metabolism); the study did not directly measure bone mineral density but note that in a related study (Chung et al., Rheumatol Int. (2005): The effect of low-dose prednisone on bone mineral density in Peruvian rheumatoid arthritis patients), although finding a reduction in hip BMD, failed to find the reduction statistically significant). However, Vestergaard et al. (J Intern Med (2005): Fracture risk associated with systemic and topical corticosteroids), again not measuring BMD but rather examining fracture risk directly, appear to confirm the Ton study findings, concluding that ingestion of more than 2.5 mg of oral prednisolone equivalents per day is associated with an increase in fracture risk, while this is not the case with inhaled corticosteroids except at daily dosages above 7.5 mg of prednisolone equivalents; not surprisingly, they found no increase in fracture risk associated with topical corticosteroids.

 

Bone Rebuilding (Osteoformative) Agents: PTH

  • Efficacy:

    Existing standard therapies for postmenopausal osteoporosis reduce fracture risk by suppressing bone resorption, but do not rebuild bone. However, parathyroid hormone (PTH), in the form of teriparatide, the recombinant 1–34 fragment of human PTH, is the first FDA-approved medication that stimulates new bone formation and resorption, resulting in the restoration of bone architecture and a clinical potential reversal of osteoporosis progression. A daily subcutaneous injection results in a net positive effect on bone mineral density (BMD) and strength. and on fracture risk reduction. See the recent reviews of Lane in Curr Opin Rheumatol:
    Parathyroid Hormone: Evolving Therapeutic Concepts), Quattrocchi & Kourlas (Clin Ther (2004): Teriparatide: A review), Cappuzzo (Ann Pharmacother (2004): Teriparatide for Severe Osteoporosis. PTH treatment recommendations have recently been incorporated into the AACE (American Association Of Clinical Endocrinologists) Medical Guidelines For Clinical Practice For The Prevention And Treatment Of Postmenopausal Osteoporosis: 2001 Edition, With Selected Updates [pdf]). See also Hodsman et al. (Endocr Rev (2005): Parathyroid Hormone and Teriparatide for the Treatment of Osteoporosis: A Review of the Evidence and Suggested Guidelines for Its Use) who conclude that at present there is no evidence that the antifracture efficacy of PTH will be superior to that of the bisphosphonates, and on this consideration advise that it be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores 3.5).

    A recent JCEM RCT study concluded that teriparatide increased BMD at most sites and decreased nonvertebral fractures more than alendronate; indeed, in this study, 3 months of teriparatide treatment increased lumbar-spine BMD to nearly the level of 12 months of alendronate treatment. Hence, anabolic agents like teriparatide represent an important new advance in the osteoporosis therapy. (See also the expert consensus opinion in the recent review by Miller et al. (Endocr Pract (2004):
    Clinical Use of Teriparatide in the Real World: Initial Insights).

  • Duration of Effect:
    A recent study reported at the 67th American College of Rheumatology (ACR) meeting (click to read) found that both teriparatide's reduction in non-vertebral fragility fractures and its effect in increasing spinal bone density remained almost three years (31 months) months after treatment termination, a promising finding given the two-year FDA mandated limit on Teriparatide use (see below, Safety).

  • Analgesic Efffect:
    Women with vertebral fractures who took teriparatide experienced significantly less back pain and fewer recurrent fractures than those not taking the drug, according to a study reported at the 67th ACR meeting (click to read). And a recent meta-analysis by Nevitt et al., Osteoporos Int (2005): Reduced risk of back pain following teriparatide treatment: a meta-analysis) found that patients on to teriparatide treatment had a reduced risk of new or worsening back pain compared to patients on placebo, HRT or alendronate. No other anti-osteoporotic agent has demonstrated a comparable ability to significantly reduce the often disabling back pain of osteoporosis that so often severely compriomises the patient's quality of life.

  • Adverse Effects:
    Side effects are primarily nausea, headache and mild non-persistent hypercalcemia, which may be dose-dependent, often presenting early in treatment; in addition, significantly more PTH recipients reported leg cramps.

  • Teriparatide + Antiresorptive Agents:
    Given that antiresorptive agents and PTH demonstrate distinct mechanisms of action, it has been speculated that the combination of these agents might exhibit significantly greater potency than either agent alone. However, the present balance of the evidence, as assessed in a recent Medscape review of the literature, is that if PTH is to be itinitiated, it should be used as monotherapy and not in combination with other antiresorptive drugs. As to the preliminary evidence on PTH following antiresorptive therapy, this tends to support the view that PTH still demonstrates a robust anabolic response following antiresorptive therapy. Further research, however, is required before definitive clinical recommendations can be supported.

    A recent study of Ettinger et al. (J Bone Miner Res (2004):
    Differential Effects of Teriparatide on BMD After Treatment With Raloxifene or Alendronate) has provided a valuable clarification of the issue of antiresortive treatment prior to teriparatide: they found that although teriparatide treatment stimulates bone turnover in patients pretreated with both raloxifene and alendronate, only prior treatment with raloxifene allows for the expected teriparatide-induced BMD increases comparable with those previously reported for treatment-naïve patients, while prior treatment with alendronate prevents increases in BMD, particularly in the first 6 months.

    Finally there is some evidence that PTH withdrawal may yield a reduction in bone mass, which appears to provide some rationale for using an anti-resorptive agent after PTH therapy (see the review in Endocrinol Metab Clin North Am: New Anabolic Therapies in Osteoporosis). This has been confirmed at least for men by Kurland et al. (Osteoporos Int:
    The Importance of Bisphosphonate Therapy in Maintaining Bone Mass in Men After Therapy with Teriparatide [Human Parathyroid Hormone(1-34)]) who conclude that "the immediate use of bisphosphonates after teriparatide withdrawal may help to optimize gains in bone density at the lumbar spine".

  • New Intermittent Regimens:
    The standard protocol for teriparatide therapy requires the osteoporotic patient to self-inject 20 micrograms daily for no more than 2 years. An early JCEM study showed the viability of an alternative dosing regimen using 28-day cycles of 75 mcg teriparatide in 30 women with osteoporosis, and more recently several animal studies have confirmed efficacy for both long-term intermittent teriparatide (Kneissel et al.) and weekly IV regimens (Okimoto et al.), as noted in the recent PT Journal review: Teriparatide for Osteoporosis: A Clinical Review). In addition, Amgen is developing PTH-Fc, and preclinical findings suggest efficacy in a twice weekly regimen. And University of Michigan researchers have developed a microsphere encapsulation delivery method that allows slow release followed by burst release of PTH over a two month cycle from a single injection (see ASMBR's Trends in Medicine). These preliminary results are highly promising for the eventual development of more convenient intermittent PTH regimens, possibly deploying oral or transdermal delivery systems.

    More recently, a promising breakthrough in PTH intermittent regimens was reported at the 25th (Sept. 2003) ASBMR (American Society for Bone and Mineral Research) Annual Meeting (see the Medscape Review for summary coverage of the ASMBR meeting). Felicia Cosman et al (Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York) presented preliminary efficacy results on a cyclic PTH treatment in which teriparatide was administered for 3 months, followed by a 3 month drug holiday, then re-administered, completing a nine-month cycle. The cyclic regimen provided an overall anabolic benefit on BMD comparable to the continuous daily regimen, despite bone formation serum markers rising and falling at the cycle points.

    This regimen addresses a potential problem associated with any PTH therapy: at commencement of treatment, it appears that bone formation is stimulated more than the resorption process, but net anabolic effectiveness may diminish within six months due to resorption stimulation "catching up" to bone formation around that juncture. It is therefore hypothesized that the holiday cycle (no PTH) may facilitate better bone formation by disallowing resorption the time needed to catch up. In addition, the cyclic regimen is likely to be more compliable with patients and healthcare insurers, while also reducing total treatment costs significantly. (Osteoporosis Watch note: (1) in this study the cyclic PTH was added to long-term alendronate treatment, and (2) no fracture data was reported).


  • PREOS:
    NPS is developing an alternate full-length human PTH (parathyroid hormone (1-84)) anti-oseoporotic drug PREOS, which recently completed a pivotal Phase III clinical trial, TOP, and for which an NDA (New Drug Application) with the FDA was filed in 2004. (An earlier trial, PaTH, has demonstrated blunting of anabolic effect under a PTH + alendronate concurrent regimen, and the ongoing POWER trial in Europe is assessing PREOS + HRT). Osteoporosis Watch has culled some preliminary rat carcinogenicity results from the standard toxicology package for submission with the PREOS NDA: in terms of the three arms of the study (low: 10, mid: 50, high: 150 micrograms of PREOS), it would appear that 10 micrograms can be identified as a non-carcinogenic dose, as incidence of osteosarcoma in this low arm was no different from that of the control arm, despite the fact that this dose is approx. 4 times that being proposed for human clinical use. In addition, dose-related bone lesion frequency in the mid- and high-dose arms would appear to be lower than those seen with teriparatide (possibly due to the presence of C-terminus responsive receptors in the PREOS full-length PTH absent in teriparatide).

    Recent studies suggest that
    parathyroid hormone (1-84) produces an increase in bone mineral density and prevents vertebral fractures (Hodsman et al., J Clin Endocrinol Metab (2003): Efficacy and Safety of Human Parathyroid Hormone-(1–84) in Increasing Bone Mineral Density in Postmenopausal Osteoporosis); Shrader, Ann Pharmacother (2005): Parathyroid Hormone (1-84) and Treatment of Osteoporosis). Fracture reduction data are pending from the TOP study.

  • Oral Calcilytic Therapy:
    The recent JCI study of Gowen et al. reports on an oral calcilytic molecule (NPS 2143) which by antagonizing the parathyroid calcium receptor stimulates PTH hormone secretion and thus increases endogenous levels of circulating PTH. Calcilytics, selective antagonists of the parathyroid cell calcium receptor, can thus promote a large increase in both bone formation and bone resorption, as well in bone turnover, comparable to that of daily oral PTH administration, and without causing parathyroid hyperplasia. This approach could represent a novel delivery system for the treatment of osteoporosis, and research in calcilytics, a novel class of anabolic agents, is likely to proceed rapidly in the pursuit of alternatives to parenterally administered PTH therapies.


  • Safety:
    Teriparatide has been issued a black box warning due to rodent carcinogenicity studies, showing an increased risk of osteosarcoma (a rare bone cancer) in rats with prolonged treatment, and consequently 2 years is the maximum recommended treatment duration. Given this, teriparatide should not be used in patients that have an increased baseline risk for developing osteosarcoma. and in patient’s with Paget’s disease, pediatric patients, and patients with a history of radiation therapy. It should also be avoided in patients that have bone metastases or a history of skeletal malignancies, non-osteoporotic metabolic bone disease, and those with pre-existing hypercalcemia.

  • Osteoporosis Watch Commentary on Safety:

    Despite the fact that the relevance of rodent ostesarcoma risk to humans is uncertain at present, it should be noted by the clinician that the well-known consumer organization Public Citizen (and publisher of Best Bills, Worst Pills), who had fought the FDA's approval of teriparatide (as Liilly's Forteo), has on the other hand found the animal data compelling, according to Dr. Larry Sasich, research analyst for the Public Citizen Health Research Group and former FDA toxicologist. Given this, the interested practitioner should consult Public Citizien's detailed Teriparatide Objections (click to read) and be prepared to discuss the issue openingly with any patient considering such treatment.

    However, in this context it should be noted that:
    (1) the PTH dose per kilogram was many factors higher than the human dose; nonetheless, Evidenncewatch does not find this point, frequently cited in defense of teriparatide's safety despite the rodent osteosarcoma results, wholly determinative on safety, for we have learned from members of the FDA's Division of Metabolic and Endocrine Drug Products (see the BMJ Letter on this) that some animals developed osteosarcomas when treated with doses that were only about three times the expected daily human exposure, a relatively small safety margin under conventional standards of modern drug development;
    (2) the therapy duration encompassed approximately 95% of rodent life span versus a proposed 2-year maximum in humans;
    (3) many aspects of the skeletal physiology , bone architecture and morphology are significantly different in rodents and humans (for example, rat bones grow in length through their entire lifetime;, while in humans, the bone ends close relatively early in life, and the rodent sarcomas developed at the bone ends, precisely where bone stops growing in late human adolescence);
    (4) furthermore, the safety study involved relatively young rats (approx. 2 months old), still undergoing substantial skeletal development over the study's term;
    (5) no induction of osteosarcoma has been evidenced in monkeys (18-month study);
    (6) there have been no human malignancies reported associated with any use of PTH (although total populations are relatively small to date, and studies are necessarily of short duration given the recency of its introduction to market);
    (7) continuous exposure to PTH in the context of human hyperparathyroidism has not evidenced any link between the common high PTH levels involved and osteosarcoma, although it must be remembered that hyperparathyroidism and therapeutic administration of PTH are not identical clinical scenarios;
    (8) the recently reported interim results of the TOP study using PREOS, an alternate full-length PTH agent (see above under PREOS) has identified a non-carcinogenic dose regimen (pending FDA approval), and this suggest some non-trivial clinical differences between full-length and fragment PTH agent forms that may be exploited to obviate the risk of osteosarcoma.

    It may be that the bone proliferative lesions in rats are not predictive of an increased cancer risk in humans when PTH is adminsitered as prescribed in clinical populations, but Osteoporosis Watch awaits further studies of sufficient power to be judged determinative in this critical arena.


    Conclusions:
    Teriparatide appears to be a novel and effective new anti-osteoporotic agent fo, and its unique osteoformative capability establishes it as an important advance in osteoporosis treatment. However, it may not be the first-line agent given the uncertainty of long-term (> 2 years) efficacy and its substantially higher cost compared to other agents currently on the market (a 30-day supply may cost in excess of over $500). Furthermore, an additional drawback is the inconvenience of a daily injection regimen, although intermittent regimens appear to be emerging. We also await further studies to resolve some open issues in safety of use in human populations and would like to see close tracking of all patient data into a monitored centralized registry; some of these issues may be addressed by emerging new formulations (possibly low-dose PREOS) and/or new intermittent or cyclic regimens, with the latter (i.e., cyclic regimen) at present appearing most promising and also at least partially resolving the PTH bone resorption stimulation problem associated with continuous daily PTH. Nonetheless teriparatide can in limited carefully selected and monitored populations be a valuable alternative in the treatment of osteoporosis when other agents lose their effectiveness or when adjunct, combination treatment is warranted in refractory or very severe/advanced cases exhibiting adverse progression.

* Osteoporosis sufferer who inspired this research, and beloved Mother-in-Law, 1915 - 2004.

Copyright © 2006. Constantine Kaniklidis. All rights reserved.