Rev Osteoporos Metab Miner. 2010; 2 (3) suplemento: 22-30
2 Hospital Universitario Insular – Servicio de Medicina Interna – Unidad Metabólica Ósea – Las Palmas de Gran Canaria
The treatment of osteoporosis in postmenopausal women consists initially of a series of non-pharmacological measures which can be applied to all patients, such as increasing where possible physical exercise, especially that which applies load, a balanced diet with sufficient calcium and vitamin D, exposure to sun for 10 minutes a day at a time when is it less strong, in addition to suppressing smoking and preventing falls1,2. However, in postmenopausal women with osteoporosis, or at high risk of developing it, to these should be added pharmacological measures.
Chronologically, the first drugs developed for the treatment of osteoporosis were the antiresorptives, among which were the oestrogens3-6, calcitonin7 and the first biphosphonates, such as etidronate8,9. All these drugs had a plausible physiopathological basis, and were the confirmation that osteoporosis produces an increase in bone resorption, checked both by the biochemical markers for bone remodelling and by bone biopsies10. Studies carried out with these drugs, as later with other antiresorptive drugs, confirmed that they produced a small increase in bone mineral density which was not related to a reduction in risk of fracture11.
In the last few years a series of drugs have been developed whose action mechanism is based on the direct stimulation of bone formation, and which, together, are called anabolic bone therapies. The objective which all these treatments pursue is the formation of new bone, the restoration of bone microarchitecture, to increase bone mineral density, and thus reduce the risk of fracture. Among these compounds are included fluorine, growth hormone (GH), insulin-related growth hormone type 1 (IGF-1), the statins, and above all, two agents which show the greatest evidence of efficacy: strontium ranelate and parathyroid hormone (PTH) and its active fragments. We focus our review on the whole molecule of PTH, known also as PTH1-84.
Bone remodelling is the term with which we refer to a constant process of renewal to which bone is subject. It takes place simultaneously in multiple microscopic well defined units, dispersed throughout the whole skeleton. In each of these units the bone is destroyed and then replaced by newly formed bone. By means of bone remodelling, the organism replaces aged or damaged bone by new tissue, and at the same time contributing to mineral homestasis12.
In osteoporosis a change in bone remodelling is produced. For reasons not yet completely known, an imbalance is produced between bone formation carried out by the osteoblasts, and the resorption or destruction of bone, for which the osteoclasts are responsible. In postmenopausal osteoporosis, there is typically an increase in bone resorption, with formation remaining steady or slightly reduced13,14. As a consequence of this, a negative balance results, which drives loss of bone mass. It is precisely the low mineral density which is the most significant risk factor for osteoporotic fractures15-18.
In the physiopathology of osteoporosis there is also a quantitative factor, which is the change in the microarchitecture in which the increase in bone turnover takes place, producing instability in the skeleton, microperforations and microfractures19-21. Even more, in practically all the clinical trials in which antiresorptive drugs, such as calcitonin, oestrogens, selective inhibitors of oestrogenic receptors (SERMs) and biphosphonates have been used, a reduction in the risk of fracture has been observed, which bears no relationship to the increase in bone mineral density11,17.
On the other hand, in diseases in which there is an excess of PTH, such as in primary hyperparathyroidism (HPT), PTH exerts a powerful anabolic effect on the bone, increasing bone formation. A group of studies has shown that treatment with PTH brings significant increases in BMD, fundamentally in the trabecular zone, as well as a reduction in the risk of both vertebral and non-vertebral fractures22. The continuous secretion of PTH, such as occurs in hyperparathyroidism, produces an increase in bone turnover, with a hyperstimulation of the osteoclasts and a net balance in favour of bone resorption. However, the intermittent administration of PTH at low doses provokes an increase in bone mass23, since it produces a stimulation of growth factors and reduces osteoblastic apoptosis, resulting in an increase in bone mass24. This dual action is what is known as the paradoxical effect25. On the other hand, to confirm this fact, Silverberg et al, have published data which shows that in asymptomatic forms of HPTP conservation of trabecular bone occurs, which results, qualitatively, in being of better quality than bone in controls of the same age and sex26-31. Similar results have been published by other authors30,32.
Taking into account these facts, it is easy to understand that treatment of osteoporosis with PTH implies a different approach to those therapies normally used up to now. PTH acts directly on the osteoblasts, given that these bone-forming cells have specific receptors for this hormone33, producing bone formation by a dual mechanism: on one hand, by the increase in the index of remodelled bone, and on the other, by obtaining a positive balance in the quantity of bone deposited in each unit of bone remodelling, as confirmed by biopsy in the increase in the trabecular thickness in the osteones. This differentiates the effect of treatment with PTH from other clinical forms with high levels of remodelling, such as occurs with oestrogen deficiency, which has a negative effect on the bone. The result is the direct production of new bone with the consequent gain in bone mineral density and reduction in risk of fracture.
Historical view of treatment with PTH
In reality, treatment of osteoporosis with PTH is not new. Already, more than 30 years ago, Reeves et al, in a preliminary study, published for the first time in the 70s a series of 4 patients to whom PTH had been administered, (the fragment1-34) at different doses (between 100 and 400 mg/day in cycles of 8 days). As a parameter to assess the effectiveness of treatment the calcium balance was used, which returned to positive in all the cases, allowing the authors to calculate the quality of the mineral deposited in the skeleton34,35. In those days densitometry was not yet available.
The same research group presented other publications, following up the same patients36,37. In spite of promising results, this research group abandoned this line of investigation. Almost a decade later, Slovik et al.38 presented a series of 8 patients treated with PTH over 12 months in whom an increase in bone mineral density (BMD) was obtained, determined through computerised axial tomography (CAT). There was also another therapeutic initiative with PTH with what is called sequential treatment, or ADFR (Activate, Depress, Free period and Repeat), proposed by Frost39. The activation phase was carried out with phosphorus, and sought the indirect release of endogenous PTH. This treatment was also abandoned.
The effects of PTH1-84 in vertebral fractures and bone mineral density in postmenopausal women with osteoporosis. The TOP study
This reference study for PTH1-84 is called the TOP (Treatment for OsteoPorosis) study, published by Greenspan et al.40. This study, which included 2,532 postmenopausal women, was carried out over 18 months in 168 centres in 9 countries. It consists of a randomised double blind clinical trial in which the women in the treatment group were administered 100 micrograms of PTH 1-84 subcutaneously, with this and the control group receiving supplements of 700 mg/day of calcium and 400 U/day of vitamin D. The baseline characteristics of this population are set out in Table 1.
The main objective was the reduction in the risk of vertebral fractures. After 18 months of treatment a decrease of 66% in the risk of new vertebral fractures was observed in the group who received treatment with PTH, a decrease which was observed both in women who had at least one previous vertebral fracture and in those who had none. Table 2 shows a summary of these results.
In the TOP study, at 18 months, the BMD increased in the lumbar spinal column by 6.9% in patients who received PTH compared to the women in the control group. The increase in BMD in the spine occurred independently of baseline BMD, age, number of years in menopause, previous treatment for osteoporosis and country. At the end of the study after 18 months, the BMD had increased in the hip by an average of 2.1% in the total hip, by 2.5% in the femoral neck and by 1.6% in the trochanter (p < 0.001 in all cases). The BMD was reduced in the extreme distal radius by 3.4% in the group treated with PTH.
Hodsman et al.41 carried out a study in 217 postmenopausal women affected by osteoporosis, with an average age of 64.5 years, to whom had been randomly administered either a placebo or PTH1-84 at doses of 50, 75 or 100 µg. This study was intended to establish the safety of treatment with PTH 1-84 and to assess changes in BMD, depending on the doses of PTH used. The study was extended for one year, at the end of which the average increase in BMD was 3.0, 5.1 and 7.8% in the groups whose doses were 50, 75 and 100 µg/day, respectively, all of which were statistically significant and clearly dose dependent, whilst in the control group, which received calcium and vitamin D, an increase of 0.9% was observed, which was not statistically significant. The increase in BMD seen in the group receiving 100 µg was statistically significant with respect to the two other groups which received PTH, the T-score of -3.2 at the start of the study moving to -2.8 at the end of it. On the other hand no statistically significant differences were seen in the BMD of the hip.
Modification of the bone cytoarchitecture after treatment with PTH 1-84
In 2005, in the absence of data in humans, with a view to studying the changes PTH 1-84 generates in bone architecture, a study was planned and carried out as randomised double blind treatment versus placebo study of biopsies of the iliac crest in postmenopausal women with osteoporosis who received daily injections of placebo or 100 µg PTH over 18 months. All the subjects received at the same time treatment with calcium (700 mg) and vitamin D (400 UI), with no significant differences between the two groups in terms of age, weight, markers for bone turnover, or BMD in vertebral column or hip.
Before being selected for the histomorphometric study, the biopsies were submitted to micro-computerised tomography to quantify the 3-D and 2-D structure of the trabecular and cortical bone, respectively. After 18 months biopsies were obtained from 8 women treated with placebo and 8 treated with PTH1-8442.
In the group treated with PTH1-84 an increase in the formation of spongy bone was observed, and in the volume of bone measured in the iliac crest, without significantly affecting bone resorption. In addition, PTH1-84 improved trabecular connectivity and restored the trabecular architecture in such a way that it changed to having a “plate” structure instead of a “rod” structure, these changes resulting from a new mechanism in which the trabeculars are first thickened and then divided by tunnels by the osteoclasts. This trabecular improvement is compatible with the marked reduction in the incidence of vertebral fractures in women treated with PTH1-84 over 18 months. The values of the structure obtained for trabecular and cortical bone were very similar between those obtained by histomorphometry and by microcomputerised tomography.
This study was carried out in 2008, lengthening the period of treatment to 24 months instead of 18 months and adding on the way a more exhaustive study of bone cytoarchitecture. For this, joining the patients of the earlier study were a sample of 7 patients, also postmenopausal women with osteoporosis who were treated with the drug in the same conditions over 24 months, and who were studied in a similar way42, evaluating the formation and structure of trabecular and cortical bone after treatment.
At 24 months, the volume of trabecular bone measured by microcomputerised tomography and histomorphometry was 45-48% higher in those subjects treated with PTH1-84 in contrast with the placebo, associated with a higher number of trabeculae and higher trabecular tunnelling and thickness. In addition, a more connected, “plate” trabecular architecture was revealed.
The index of trabecular formation (BFR) was 2 times higher in those patients treated with PTH given the greater surface of mineralisation. The osteoblastic and osteoclastic surfaces were 58% and 35% higher, although these parameters did not end up being significant, whereas neither the surface of osteoclasts nor the cortical, endocortical or periostic thickness, were modified with PTH treatment, even though cortical porosity was higher.
It was observed also that, although the formation of trabecular bone was lower after the 24 months of treatment, the measures of the structure of the trabecular and cortical bone were the same in both periods. The bone formed as a result of the treatment with PTH1-84 had a normal lamellar structure and mineralisation, without any signs of abnormal histology.
As a conclusion, coinciding with that stated earlier, treatment with PTH increases the volume of trabecular bone, as well as its “plate” structure, and this is related with a lower incidence of fractures43.
Biochemical markers for remodelled bone
Due to its anabolic action, the administration of PTH 1-84 produced in the TOP study an increase in the biochemical markers for remodelled bone, specifically bone alkaline phosphatase, barely a month after the start of treatment. The markers for bone resorption were not modified at the start and only modified after at least 6 months had passed from the start of treatment, at which point an increase in urinary collagen type 1 N-telepeptide was observed. This suggests that PTH 1-84 produces an increase in osteoblastic activity at the start, which, at a later stage increases bone resorption. The markers for remodelled bone remain increased after 18 months of treatment, findings which were consistent with those seen in the bone biopsies obtained from the iliac crests of those patients, in which were observed an approximate doubling in the indices of bone formation40. In the PaTH study, to which we refer later, it was observed that the administration of PTH 1-84 produced an increase in biochemical markers for bone formation, specifically of PINP, in months 1, 3 and 12 of 80, 140 and 157%, while blood levels of bone alkaline phosphatase, another marker for bone formation, increased by 22, 46 and 63% over the same period of time. On the other hand, the increase observed in the biochemical markers for bone resorption, specifically blood CTX was 5, 64 and 109% respectively44. The point in time at which these changes happen reinforce the hypothesis that the action of PTH is initially anabolic to start with and that later, after approximately 6 months, it produces an activation of the osteoclasts as part of the cycle of remodelled bone.
PTH 1-84 in combined therapy
In the PaTH study, Black et al.45 analysed the effect that PTH1-84 had on BMD, alone, combined with alendronate and with alendronate alone. After a year of follow up, it was found that BMD increased in the lumbar spine in the three groups treated, without statistically significant differences between the group on PTH alone and that which combined PTH and alendronate, and the volumetric density, measured by computerised axial tomography, also increased significantly in the two groups which received PTH. However, the markers for bone formation did not increase in the group which combined PTH with alendronate. When the markers for bone resorption were analysed they were reduced in those to whom alendronate was administered. The authors concluded that the combine treatment with PTH1-84 with alendronate did not have a synergenic effect, a point which was commented on in detail in an editorial by Khosla46, and which, at the time generated considerable controversy.
Another similar study was carried out by Fogelman et al.47, who combined PTH1-84 in postmenopausal women who were receiving hormone replacement therapy. It is a study in which few women participated (only 187 patients were randomised). However, at its conclusion after 2 years the authors found that the women who had received HRT and PTH had obtained higher increases in BMD than those who had received HRT and placebo. However, subsequently, Vestergaard et al.48 published a meta-analysis in which the effect of PTH alone or in combination with other drugs was studied, both on bone mineral density and in the reduction in risk of fracture. The authors reached the conclusion that, although the number of studies on non-vertebral fractures is limited, the aggregated data indicated that PTH administered alone or in combination with antiresorptive drugs would be capable of reducing the risk of vertebral and non-vertebral fractures and of increasing the BMD in the lumbar spine and perhaps in the hip. However, the authors indicated that the results had been obtained on the basis of transversal studies and that more studies are necessary to be able to a definitive conclusion to be reached, and that the superiority of PTH combined with an antiresorptive as opposed to PTH alone with respect to BMD and a reduction in the risk of fracture could not be established.
But, on the other hand, in addition to the combined therapy which we have just analysed (which consists of administering both drugs at the same time), sequential therapy was tried, in which first PTH 1-84 is administered as an anabolic drug, attempting to obtain the maximum gain possible, for a subsequent second phase after suspending the PTH, of administering an antiresorptive. Thus, a study carried out by Rittmaster et al.49, studied a group of 66 women who had received PTH 1-84 at doses of 50, 75, and 100 µg /day over one year and after suspending this treatment, were then administered 10 mg/day of alendronate for one more year. During the first year the BMD in all the women (at all the different doses of PTH) increased by 7.1 ± 5.6% in the lumbar spine, by 0.3 ± 6.2% in the femoral neck and by 22.3 ± 3.3% in the whole body. After moving on to the alendronate, at the end of one year the changes in bone mineral density were 13.4 ± 6.4% in the lumbar spine, 4.4 ± 7.2% in the femoral neck and 2.6 ± 3.1% in the whole body. In the subgroup of patients who received the highest dose of PTH, the average increase in BMD in the lumbar spine was 14.6 ± 7.9%. While the treatment with PTH was maintained the biochemical markers for remodelled bone remained at increased levels and decreased to below the initial value after the year on alendronate.
Efficacy and safety of PTH 1-84 in prolonged therapy
We have seen, to this point, that therapy with PTH 1-84, both on its own and combined, is efficacious. However, there is still argument about for how long a period it can be administered with safety and efficacy for the treatment of osteoporosis. Studies such as TOP40, talk of a proven efficacy at 18 months, although there is discussion of whether at 24 or even 36 months PTH1-84 still maintains its efficacy, without causing serious consequences which impede the use of the drug. In fact in our country, PTH1-84 is approved for use for 24 months. The parameters most often used to measure the efficacy of the drug over the period of treatment has been, on the one hand, the determination of the markers for remodelled bone, whose changes are correlated with expected action of this type of bone-forming agent, of which the most important is the elevation in bone alkaline phosphatase and the N telopeptides of collagen type 1. The other parameter for the evaluation of efficacy is the reduction in risk of fracture after treatment. On the other hand, to evaluate safety, reference has been made both to the reasons for the rejection of treatment as well as histological studies obtained through trabecular and cortical bone biopsy in long term treatments.
Recalling the conclusions of the TOP study40, it could be demonstrated that the administration of 100 micrograms of PTH daily over 18 months, resulted in a therapy efficacious both in the prevention of new fractures and in preventing the worsening of existing fractures in postmenopausal women with osteoporosis. The raised levels of markers for remodelled bone, more specifically bone alkaline phosphatase, was already evident from the first month of treatment, and this elevation was significant in comparison with the placebo group. This did not happen in the same way with the N telopeptides of collagen type 1, although at 6 months levels of both were significantly raised. The most important point is that at the end of 18 months, levels of these markers remained elevated, which perhaps suggests that the drug could continue to act beyond the period covered in the study.
It is for this reason that, subsequently, it was decided to carry out a prolongation of this study, with women who had participated in it, in whom treatment with PTH was extended until they had completed 24 months of treatment. Reference is made here to the OLES study50, in which subjects whose adherence to treatment had been 80% were compared with those who had presented less than 80% adherence to treatment. It was observed that at 24 months that the BMD in the lumbar spine those whose adherence was over 80%, was 8.4% higher than that achieved after 18 months of treatment, recorded at the end of the TOP study, and that those subjects with less than 80% adherence succeeded in surpassing those in the TOP study by 4.5%. In the femoral neck, levels 2.6% and 1.5% higher respectively were attained. In terms of the markers for remodelled bone, while a decrease in its levels from months 12-18 could be seen, it could also be observed that in month 24 they would remain raised, or even become higher than those recorded at the end of the TOP study, showing that PTH1-84 continues to maintain its efficacy after 24 months.
The TRES study (Treatment Extension Study), gathered data from the extension of this treatment, two months after the OLES study in women in whom treatment with PTH1-84 was prolonged at the same dose, for a total of 36 months. Although it should be noted that in this period of two months between studies there was a slight reduction in BMD, which it is thought could be due to the interruption in treatment, the results obtained after 36 months showed an increase of 8.5% above the levels of BMD measured in the lumbar spine in the OLES study, as well as a 3.2% increase in the hip and 3.4% in the femoral neck, with the conclusion that the BMD continues to increase, even after 36 months of treatment with PTH1-84.
With regard to the safety of the drug at 36 months in terms of bone histomorphology, the results obtained in the TRES study were collated by the group led by Recker et al.51, concluding that the treatment with PTH1-84 of postmenopausal women with osteoporosis was generally well tolerated, with the biopsies obtained from the trabecular and cortical bone not being pathological. This all suggests that even at 36 months of treatment PTH1-84 continues to be beneficial in the treatment of osteoporosis.
Adverse effects of treatment with PTH 1-84
While the efficacy of treatment with PTH1-84 as an alternative to antiresorptive agents used until now against osteoporosis has been proven, it is worth mentioning that there is in turn, a series of frequent adverse effects, which, although on occasion have meant withdrawal the subjects studied which may result in modifying the results, can be resolved.
The adverse physical effects produced due to treatment with the drug are mostly mild40,45, the most common being hypercalcemia, present in 28% of women treated as opposed to 4.6% in the placebo group, and hypercalciuria in 46% and 23% respectively. However, the number of withdrawals from treatment for this reason was small in the clinical trials published (two patients in the PaTH study and six patients in the TOP study) and generally the effect is controlled by withdrawing the calcium and vitamin D supplements which the patients are receiving without requiring a reduction in the dose or withdrawing treatment.
The electrocardiographic studies give similar results in both groups with no significant variation observed in relation to studies carried out at the start of the period of treatment, although it is thought that hypercalcemia may slightly modify these results by diminishing the QT interval, without significant changes, or minimal variations, in cardiac frequency, the PR interval or the duration and axis of the QRS. Other adverse effects described, although infrequent and not of equal importance to those mentioned earlier, were nausea and vomiting.
The reason for which the period of use of PTH is limited was the appearance of a few cases of osteosarcoma in rats, at doses much higher than those used for treatment. These occurred only in rats (Table 3). No increase in the incidence of osteosarcoma, or any other type of tumour, have been detected in humans. Recently Tashjian et al. reported that they have not recorded a single case of osteosarcoma in humans, after the prescription of more than 250,000 treatments with PTH, both 1-34 and 1-84 intact, or even after following up the patients who participated in studies with PTH1-84 in the 1980s52-54.
What is the role of PTH 1-84 in the treatment of osteoporosis?
PTH1-84 reduces the risk of vertebral fracture, both in patients who had a previous vertebral fracture and in those who did not. Given its price, and the necessity of daily parenteral administration, it is a drug which should be used in patients with a high risk of fracture or when there is no possibility of using the drug of first choice, such as alendronate, risedronate or zoledronate, in accordance with SEIOMM’s clinical guides of55.
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