EXPLAIN IN DETAIL THE VARIOUS PHARMACOLOGICAL OPTIONS FOR THE TREATMENT OF OSTEOPOROSIS ?
A 1 INTRODUCTION
1 osteoporosis is the most common bone disease, associated with low bone mineral density (BMD) and pathological fractures which lead to significant morbidity.
2 It is defined clinically by a BMD of 2.5 standard deviations or more below the young female adult mean (T-score =−2.5).
PHYSIOLOGICAL BASIS
1 Healthy skeleton is maintained throughout life by the constant process of bone remodeling that is regulated by the balanced activities of bone-resorbing osteoclasts and bone-forming osteoblasts to maintain normal physiological structure and mineral content.
2 The bone remodeling process is completed in 4–6 months.
3 It takes place mostly in a nontargeted manner to remove old bone ( V IMP ) and involves resorption of bone by peripheral blood-derived multinucleated osteoclasts, followed by bone formation by osteoblasts
4 Remodeling also takes place at specific, targeted bone surfaces, which develop stress-induced microfractures attracting osteoclasts by signaling via osteocytes embedded deep within the mineralized bone.
5 The activation of different bone cells in the bone remodeling process is orchestrated by multiple pathways such as receptor activator of nuclear factor (NF)-κB ligand (RANKL) and Wnt signaling pathways, and these pathways are exploited in the development of new therapies for osteoporosis *** VV IMP
ETIOLOGY
1 Osteoporosis is caused by an uncoupling of bone resorption from bone formation such that the activities of osteoclasts far outweigh those of the osteoblasts.
2 Peak bone mass is achieved in early adulthood and, following this point, both women and men lose bone with increasing age.
A ) However, this process is accelerated in postmenopausal women whereby the loss of estrogen is associated with an increase in osteoclast activity.
B ) estrogen plays a dominant multifactorial role in maintaining cortical bone formation by supporting osteoblasts and preventing bone resorption by suppressing osteoclast formation and stimulating osteoclast apoptosis ( similar function of testosterone )
3 Secondary osteoporosis is defined as osteoporosis that develops as a consequence of an unrelated underlying cause
A ) These can include a drug treatment
1 chronic corticosteroid use
2 hypogonadism
3 malnutrition
4 eating disorders such as anorexia nervosa
5 excessive exercise
6 neoplastic disorders.
4 The integrity of the skeleton is also intricately linked to appetite and energy balance, and the underlying mechanism by which bone mass is regulated by the brain is through a leptin-mediated brain-derived serotonin pathway
A ) There is potential adverse effects of anti-obesity leptin therapy on bone mass and confirms the molecular basis of the bone loss that is associated with prolonged treatment with selective serotonin reuptake inhibitors ( vv imp )
VARIOUS OPTIONS FOR PHARMACOTHERAPY IN OSTEOPOROSIS
A ) ANTI RESORPTIVE DRUGS
1 BISPHOSPHONATES -
A ) are the most commonly used drugs for the treatment of osteoporosis.
B ) MODE OF ACTION
vv imp - They avidly bind to bone and are internalized by osteoclasts to inhibit resorption .
C ) They are administered both orally and intravenously and are divided into two classes –
A ) the low potency non-nitrogen containing bisphosphonates and
B ) the potent nitrogen-containing bisphosphonates.
1 These two classes have distinct intracellular targets and molecular mechanisms of action that lead to inhibition of osteoclast-mediated bone resorption
2 All bisphosphonates have a phosphate-carbon-phosphate backbone with two side chains (R1 and R2).
A ) The non-nitrogen containing bisphosphonates have simple side chains (in etidronate R1 and R2 are CH3 groups, in clodronate R1 and R2 are Cl groups) and are metabolized in osteoclasts to non-hydrolysable analogs of adenosine triphosphate (ATP), accumulation of which causes osteoclast apoptosis ( vv imp - mcq )
B ) On the route to clinic, etidronate successfully administered to treat a young patient with myosytis ossificans progressive in 1968, and prior to the use of etidronate (Didronel®) as an anti-osteoporotic drug it was used to treat Paget’s disease of bone before Procter and Gamble developed it for treatment of osteoporosis.
C ) In the nitrogen-containing bisphosphonates, R1 tends to be –OH and R2 contains a nitrogen molecule either attached to a multiple carbon side-chain (as in alendronate and pamidronate) or in a heterocyclic group (such as risedronate and zoledronate).
1 - These bisphosphonates are not metabolized to non-hydrolysable ATP analogs but inhibit farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate pathway.
2 - In addition to cholesterol biosynthesis, this pathway is responsible for synthesis of farnesyl and geranylgeranyl pyrophosphate, required for the prenylation and correct subcellular localization of proteins, including small GTPases that regulate processes critical for osteoclast function, including vesicular trafficking
3 - The potency of nitrogen-containing bisphosphonates for inhibiting FPPS activity correlates with their ability to inhibit resorption in vivo.
EG -
1 - Alendronate (Fosamax®; oral, 70 mg) is the most commonly prescribed drug for the treatment of postmenopausal osteoporosis and is associated with increased BMD and fracture risk reduction.
A ) Oral bisphosphonates but especially alendronate are associated with gastrointestinal side effects, despite detailed guidance on when and how to take the medication.
2 and 3 Risedronate (Actonel®) and etidronate (Didronel®) are recommended for patients who are unable to tolerate alendronate.
A ) These side effects are likely one of the reasons for patient noncompliance with oral bisphosphonates.
4 ( mcq ) Intravenous administration of other nitrogen-containing bisphosphonates (pamidronate, zoledronate) overcomes this patient non-compliance, and a 5 mg dose of zoledronate (Aclasta®) is highly effective at reducing fracture risk and preventing new fractures if administered as an annual single infusion.
A ) It is approved for use in women at high risk of fracture or who have experienced a previous osteoporotic fracture. Intravenous bisphosphonates are generally well tolerated, and the most commonly observed side effect is self-limiting flu-like symptoms which persist for about 3 days following the first administration, mediated by circulating monocytes and activation of specific subsets of T-cells.
ADVERSE EFFECTS
1 Vv imp ( Osteonecrosis of the jaw (ONJ) is a rare but recognized side effect resulting from long-term bisphosphonate use )
A ) The estimated rates of occurrence in osteoporosis patients taking oral bisphosphonates range from 1/100,000 to 1/10,000 patient years of oral bisphosphonate administration.
B ) The route of administration of bisphosphonate and duration of treatment affects the projected time to onset of ONJ (median time of 3 years for intravenous and 5 years for oral) and may explain why ONJ is more common in cancer patients receiving higher doses of intravenous zoledronate than in osteoporosis patients whose first-line therapy is oral alendronate ( vv imp )
2 - Accumulating evidence suggests that long-term use of bisphosphonates is associated with atypical fracture of the femur, diagnosed upon presentation with a characteristic combination of features to distinguish from typical femoral fractures.
A ) Recommendations by the FDA in 2010 advised that bisphosphonate labeling be changed to raise awareness of the potential increased risk of such fractures with extended bisphosphonate use.
B ) The pathophysiologic mechanism of this unique type of fracture is likely to be related to the affinity of bisphosphonates for areas of increased bone remodeling, thus accumulating in high concentration in bone matrix.
1 - This means prolonged absence of osteoclast activity, which by virtue of the tight coupling of osteoblast to osteoclast activity will result in a subsequent inability of osteoblasts to repair microdamage
2 There have been a few reports of cases of treatment failure or incidence of fragility fracture in patients taking anti-osteoporotic medications, particularly bisphosphonates.
3 VV IMP This group of patients was categorized as nonresponsive or resistant to bisphosphonate treatment, and it would be interesting to determine whether this nonresponsiveness was a result of genetic differences.
4 A single nucleotide polymorphism (rs2297480) within the promoter region of FPPS was recently associated with low BMD and reduced response to bisphosphonate treatment in postmenopausal women, with carriers of the rare allele demonstrating significantly less improvement in BMD with long-term bisphosphonate treatment compared with homozygous carriers of the common allele.
5 It was suggested that the variant allele destroys a Runx1 binding site, likely leading to increased FPPS transcription.
2 - DENOSUMAB
A ) The interaction of RANKL with RANK is critical for the formation and function of bone-resorbing osteoclasts.
B ) Denosumab (Prolia®), a fully human monoclonal antibody against RANKL, is an anti-resorptive drug that acts by preventing RANKL from interacting with RANK on the osteoclast precursor cells
1 This inhibits the differentiation and function of these cells and is associated with fracture prevention at multiple sites
2 In 2010, denosumab (60 mg, subcutaneous injection every 6 months) was licensed by the FDA for use in postmenopausal women who are at high risk of osteoporotic fracture and for those that have been nonresponsive to other osteoporosis therapies.
3 In 2012, it was approved for treatment of osteoporosis in men with high risk of fracture. When the effectiveness of denosumab and alendronate treatment in postmenopausal women was compared, denosumab was at least as effective at increasing BMD at the hip and lumbar spine.
4 Although clinical effectiveness was maintained for up to 6 months following a single injection of denosumab, cessation of treatment was associated with a more rapid reduction in BMD compared with bisphosphonate therapy,
5 since unlike bisphosphonates, denosumab is not incorporated into the structure of the bone itself and therefore resolution of denosumab-associated ONJ may be more rapid than bisphosphonate-induced ONJ if treatment is stopped ****
2 CALCITONIN
NO LONGER USE OWING TO DEVELOPMENT OF CANCER
3 ANABOLIC AGENTS
A ) Teriparatide
1 Parathyroid hormone ( PTH) plays a central role in calcium homeostasis by maintaining the serum calcium level within the physiological range by indirectly (via osteoblasts) stimulating osteoclasts to resorb bone.
2 Although in hyperparathyroidism this catabolic effect leads to loss of bone mineral content, PTH has an anabolic effect on bone remodeling when administered intermittently.
3 Teriparatide (1–34 amino acid peptide) is a human PTH analog which also has an osteoanabolic effect when administered intermittently at low doses.
4 Teriparatide (Forteo®) is effective (20 μg/day subcutaneously) at increasing BMD in postmenopausal and glucocorticoid-induced osteoporosis and is more effective than alendronate at reducing the incidence of vertebral and hip fractures.
5 Both the pro-resorptive and anabolic functions of teriparatide are required for clinical effectiveness.
Vv imp 6 Combining anti-resorptive therapy (to inhibit bone loss) with teriparatide therapy (to stimulate bone formation) has agent-specific effects on the overall effectiveness of teriparatide therapy.
7 The administration of raloxifene prior to teriparatide improves BMD above that of teriparatide alone.
A ) IN COMPARISN -
IN A REVIEW
1 - In open-label studies, alendronate blunted the ability of teriparatide to increase BMD when the therapies were combined
2 - whereas in another study patients that had been previously treated with risedronate showed better improvement in BMD in response to teriparatide than patients that had previously been on alendronate therapy.
3 Randomized trials that examined the effect of combining PTH (1–84) itself with alendronate showed no synergistic effects on BMD at multiple sites.
4 However, if patients that had taken PTH (1–84) for 1 year were randomized to alendronate, they showed significant improvement in BMD.
5 Recently, a pilot randomized study examining the effect of concurrent or sequential administration of ibandronate with just 6 months PTH (1–84) demonstrated overall improvements in BMD but with a blunting of the anabolic effect of PTH.
6 Taken together, these data demonstrate that more studies are needed to clarify the most appropriate combination therapies to best exploit the anabolic potential of intermittent PTH-based therapies.
MECHANISM OF ACTION
A ) The exact mechanism leading to the anabolic effect of teriparatide is not fully understood, but it has been shown to enhance osteoblast formation from its circulating precursors and prevent osteoblast apoptosis.
B ) Despite its anabolic effect on bone, the use of teriparatide in osteoporosis remains guarded due to the associated high incidence of osteosarcoma in animal models; however, a long-term clinical study has so far found no association between osteosarcoma and teriparatide in humans.
C ) Teriparatide is approved by the FDA as an anabolic treatment for osteoporosis in individuals at high risk of fracture.
D ) The potential to reduce the frequency of administration (and hence increase compliance) is a possibility given that a single 20 μg dose of teriparatide is effective for up to 1 week
E ) In addition, alternative delivery systems (such as intranasal and transdermal) are currently being tested, and an implantable wirelessly controlled drug delivery device for teriparatide is in clinical trial for postmenopausal osteoporosis.
B ) Strontium ranelate
1 - Divalent strontium ions have the capacity to substitute for calcium within bone without adversely affecting mineralization.
2 - Strontium ranelate (Protelos®) increases BMD and reduces the risk of vertebral and nonvertebral fractures.
3 The protective effect of strontium ranelate results from an uncoupling of bone formation from resorption, thereby increasing functional osteoblasts whilst simultaneously decreasing osteoclasts
4 The mechanism by which strontium has these concomitant effects is thought to involve, at least in part, the calcium sensing receptor (CaSR) , the receptor responsible for mediating cellular responses to extracellular calcium ions.However, there is also evidence for CaSR independent pathways.
5 Strontium ranelate is not approved by the FDA, but is licensed (oral formulation of 2 g/day) for restricted use for the prevention of vertebral and nonvertebral osteoporotic fractures in the EU, in patients where bisphosphonate treatment has failed or is contraindicated.
6 The prescribing guidelines have been amended recently to account for reported adverse effects of strontium ranelate treatment, including skin rashes and deep vein thrombosis.
C ) Raloxifene
1 To overcome the potential unwanted tissue-specific effects of estrogen, selective estrogen receptor modulators (SERMs) were investigated for a potential role in osteoporosis management.
2 Tamoxifen, used to treat breast cancer, also has beneficial effects on BMD, and raloxifene hydrochloride (Evista®) improves BMD in postmenopausal women and was approved by the FDA for use in the prevention of osteoporosis in postmenopausal women in 1997.
3 In the EVA (Evista vs Alendronate) trial, a direct comparison with daily oral alendronate (10 mg) demonstrated that daily oral raloxifene (60 mg) was equally as effective at reducing fracture risk; however, this study was terminated early because of slow enrollment, so the numbers in the final analyses were low.
4 A recent retrospective database analysis found similar improvements in fracture rates in alendronate versus raloxifene-treated cohorts, with reduced risk of breast cancer in the raloxifene-treated patients.
5 Side effects of raloxifene treatment include an increased risk of fatal stroke and venous thromboembolism that were observed in the RUTH trials.
6 Given that raloxifene is also effective at reducing the risk of developing breast cancer, the FDA subsequently approved it in 2007 for treatment of postmenopausal women with high risk of breast cancer.
7 In addition to synthetic SERMs, there is increasing interest in the therapeutic application of naturally occurring phytoestrogens in the regulation of bone remodeling and prevention of bone loss.
A ) One example is genistein, an isoflavone found in soybeans that effectively prevents postmenopausal bone loss without adverse effects on other tissues.However, the overall effectiveness of phytoestrogens on fracture risk has not been proven.
NEW TREATMENT - ADVANCED - LATEST INTERVENTION
1 Anti-sclerostin antibodies
A ) Sclerostin is expressed by osteocytes, secreted as a monomer, and was first identified as the gene mutated in sclerosteosis, a disease featuring hyperostotic bones
B ) Sclerostin is a negative regulator of bone formation by antagonizing the interaction between Wnt ligand and LRP5/6 co-receptor on osteoblasts, thus inhibiting canonical Wnt signaling.
C ) Sclerostin expression is upregulated during mechanical unloading, which is associated with reduced BMD, and sclerostin antibodies prevent bone loss associated with unloading in mice.
1 - Phase I trials of AMG785 (a humanized monoclonal antibody against sclerostin) showed increase in bone formation and reduction in bone resorption markers in healthy men and postmenopausal women, and Phase II trials are underway (NCT00896532).
2 - AMG 167 (also a humanized monoclonal antibody against sclerostin) has completed Phase I clinical trials for the treatment of osteopenia (NCT01101048; results pending).
2 Cathepsin K inhibitors
A ) Cathepsin K was first cloned from a human cDNA library in 1995, and expression was localized predominantly to osteoclastoma tissue
B ) It is a lysosomal cysteine protease released by osteoclasts across the ruffled border during bone resorption and catalyses the degradation of type I collagen.
C ) Nonsense mutations in cathepsin K were identified in patients with pycnodysostosis, a disease characterized by nonfunctioning osteoclasts, and it was this together with the osteopetrotic phenotype of Ctsk−/− mice that confirmed cathepsin K as a possible therapeutic target for osteoporosis.
D ) A number of cathepsin K inhibitors have been developed, and most to date have been discontinued as a result of adverse reactions due to lack of selectivity or drug interactions.
1 - Odanacatib is a selective, reversible nonpeptidic biaryl inhibitor of cathepsin K, which is effective at increasing BMD with 50 mg weekly doses, given a relatively long half-life (up to 93 hours).
2 - Odanacatib reduces bone resorption whilst maintaining bone formation – an uncoupling of bone formation from resorption likely as a result of the fact that cathepsin K inhibition does not reduce osteoclast numbers and therefore osteoclast–osteoblast coupling factors (such as the ephrins) have the potential to maintain osteoblast recruitment and function.
3 Odanacatib has reached Phase III clinical trials in postmenopausal women (NCT00529373 and NCT00729183). In 2012, Medivir AB (Switzerland) commenced a Phase I trial of their lead cathepsin K inhibitor MIV-711.
3 Stem cell therapy
1 Over recent years, stem cell therapy in musculoskeletal research has exploded, and there is a wide range of possible clinical applications for such technologies, many focusing on tissue repair following damage, including bone fractures, cartilage lesions, or ligament and tendon injuries.
2 One hurdle in the development of therapies exploiting endogenous mesenchymal stem cells (MSCs) is their lack of capacity to home to bone surfaces.
3 VV IMP A recent study indicated the possibility of directing endogenous MSCs to the bone surface using piggyback technology in which LLPA2, the ligand for integrin α4β1 expressed by MSCs, is administered in vivo, piggybacked onto alendronate.
A ) When LLPA2 binds to MSCs, the bisphosphonate directs those stem cells to the bone surface where osteoblastic differentiation and subsequent bone regeneration takes place.
B ) In studies in mice, this approach was effective when employed to direct transplanted MSCs to the bone surface, and the results strongly indicated that the homing of endogenous MSCs was positively influenced too.126
Treatment guidelines
A ) In men, specific guidelines are not published, however the Endocrine Society suggest a guideline for pharmacological treatment of osteoporosis in men based on a T-score of −1 or below and FRAX® scoring.
B ) Elderly men with low serum testosterone and a risk of fracture are advised to take testosterone and a bone protective drug such as bisphosphonate or teriparatide. Any improvement in treatment can be monitored every 1–2 years.
C ) a recent report from the FDA, it was suggested that, based on evidence from three long-term clinical trials, patients are unlikely to benefit from continued treatment with bisphosphonates beyond 3–5 years, and it was difficult to predict how long the beneficial effect of bisphosphonates would remain after discontinuation of therapy
CONCLUSION
1 Currently, bisphosphonates are the mainstay treatment for osteoporosis. Although there are concerns about their long-term effect, they are one of the safest drugs because of very short serum half-life (4 mg/5 min intravenous infusion reaching less than 1% of initial serum concentration at 24 hours postadministration) and high tissue specificity.
2 Moreover, since alendronate is now off-license and therefore a generic drug, it is far cheaper compared with other available treatments for osteoporosis.