BoneKEy-Osteovision | Commentary
Intermittent parathyroid hormone: Bones key to regaining its mass, architecture and strength
DOI:10.1138/2001033
SummaryAntiresorptive agents increase the mineral content of existing bone; the amount of bone tissue does not increase. When administered intermittently, parathyroid hormone (PTH) builds bone by stimulating periosteal and endosteal apposition and so increases bone diameter, cortical and trabecular thickness, and perhaps trabecular numbers and connectivity. These structural changes probably account for the increased bone strength reported in animal studies and the reduction in spine and non-spine fractures recently reported in women with postmenopausal osteoporosis. Although published data in humans are unavailable, in animals, withdrawal of PTH results in the loss of these structural changes. However, when antiresorptive agents are given following PTH, the structural changes are largely maintained. PTH administration is likely to offer a means of restoring the structural and biomechanical integrity of the aged skeleton, and as such is a most important advance in the treatment of osteoporosis.
The loss of bone mass and mineral mass during advancing age Bone gets younger as it gets olderThis is not the Never Never Land and there is unlikely to be a timeless magical period of ‘stability’ where Peter Pan and Wendy neither growth nor age. Ageing of the skeleton regrettably begins at about the end of the second decade and is accompanied by a fall in bone mass (). Bone mass decreases because the volume of bone removed by osteoclasts is greater than the volume of bone replaced by osteoblasts during the remodeling cycle. This negative bone balance at the remodeling site or basic multicellular unit (BMU) begins well before menopause, perhaps just after completion of growth. It is the structural basis of bone loss and the progressive erosion of skeletal architecture which are characterized by cortical thinning, intracortical porosity, trabecular thinning and loss of connectivity. Whether the imbalance increases with age is unknown because histomorphometric studies have not been done in young adulthood. Nor is there data examining the cellular basis for the increase resorption depth and reduced bone formation in BMU.
In midlife, bone remodeling increases in women. The accelerated loss of bone is the sum of the negative bone balance within the larger numbers of remodeling sites bombarding the surfaces of the skeleton eroding it in a hail storm unleashed by estrogen deficiency. Estrogen deficiency may also make the BMU imbalance more negative by increasing the life span of the osteoclast so that it digs a deeper lacuna, and decreases the life span of the osteoblast, and so, the amount of bone formed in the deeper lacuna ().
In addition to the loss of bone mass produced by the resorption-formation imbalance, there is loss of mineral mass as the more densely mineralized older bone is replaced with younger more ‘lightly’ mineralized bone (like the soft green of an early spring leaf). In high remodeling states an increasing proportion of bone is younger and its mineral content is lower - bone gets younger as it gets older. Thus, there are three mechanisms increasing the loss of bone mass and its mineral content - an increase in the activation frequency or remodeling rate, a more negative bone balance within each of the greater numbers of remodeling sites, and less bone mineral within each BMU as younger bone replaces older bone.
Antiresorptives increase the mineral content of the more slowly diminishing mass of boneAntiresorptive agents reduce the rate at which bone is remodeled. Fewer sites excavate bone on its endosteal (trabecular, endocortical, intracortical) surfaces so that less of the existing volume of the mineralized skeleton is ‘turned over’. Remodeling and turnover are not synonymous and should not be used interchangeably. The reduced remodeling rate results in a slowing of the rate of occurrence of trabecular thinning and perforation, cortical thinning, and porosity. The reduced turnover of the skeletal mass results in an increase the mineral content of the existing bone. Older osteons at various stages of secondary mineralization are no longer removed and replaced by young bone. Instead they undergo more complete secondary mineralization becoming more densely laden with mineral (like the deep green of a late summer leaf). Antiresorptives may also reduce the magnitude of the BMU imbalance by reducing the lifespan of the osteoclast and increasing the life span of the osteoblast.
Thus, the antiresorptive agents do tackle the three mechanisms causing bone loss. They reduce the rate of remodeling, they may reduce the negative balance in the BMU, and they increase the mineral content of the bone. However, there is no evidence that these drugs eliminate the negative bone balance or make it positive. The latter, if it occurred frequently enough, would thicken the cortices and trabeculae; unfortunately, the slow remodeling rate makes this unlikely.
This class of drugs does slow the progression of bone fragility by reducing the remodeling rate but at no stage is there an increase in bone mass. On the contrary, the bone mass continues to decrease, albeit more slowly, while its mineral content increases because bone turnover is reduced. The increase in mineral content of the existing bone may partly account for the early reduction in fracture risk. Whether the continued increase in the mineral content reduces - or increases bone fragility - in the longer term is uncertain (). The point is, antiresorptive agents do not restore the strength of bone by increasing its mass and re-fashioning this mass into its pristine architectural form
The doctors dilemma - “stimulate the phagocyte”Parathyroid hormone achieved its reputation as a powerful antiresorptive agent in a blinkered world obsessed with increased bone resorption and quite unprepared to receive the knowledge of its more profound talents as a stimulator of bone formation; an observation reported by Bauer and the fuller all bright light in 1929 (). George Bernard Shaw recognized the need to stimulate bone formation even earlier, in 1906. He was close; ‘stimulate’ - yes, the phagocyte - no ().
Intermittent PTH builds boneMost studies in postmenopausal women are published in abstract form only but report that PTH increases periosteal and endocortical bone formation, total bone area, cortical area, polar and axial moments of inertia and torsional strength (). However, there is a great deal of supporting evidence in animals made osteoporotic by gonadectomy or immobilization showing that intermittent PTH(1-34) or the analog SDZ PTS 893 increase cortical and trabecular bone volume. Cortical bone strength is increased by PTH- stimulated periosteal and endocortical apposition, which increases bone diameter and cortical thickness above gonadectomized and sham operated controls (). PTH increases cancellous bone formation rate, mineral appositional rate and trabecular thickness. Increased trabecular numbers and connectivity are reported in some studies. Trabecular numbers may increase by longitudinal tunneling of thickened individual trabeculae.
Intermittent PTH reduces fracture riskThe bottom line is antifracture efficacy. Recently published is the only rigorously designed and executed study with antifracture efficacy as an endpoint. Neer et al. randomly assigned 1637 postmenopausal women with prior vertebral fractures to 20 or 40 µ g subcutaneous recombinant human PTH (1-34) or placebo daily during a median of 19 months (). New vertebral fractures occurred in 14% (placebo), in 5% (20 µ g) and in 4% (40 µ g) of patients; with a risk reduction of 0.35 (95% CI, 0.22 - 0.55) and 0.31 (0.19 - 0.50) for the respective doses. Nonvertebral fractures occurred in 6% (placebo) and 3% of patients in each treatment arm, providing a risk reduction of 0.47 (0.25 - 0.88) and 0.46 (0.25 - 0.86) respectively. The study was well designed and executed with few drop-outs and few, if any, serious side effects.
Inference is always a leap of faith and can be made with greater confidence when observations are replicated. There is one other study in humans that supports the observations. Cosman et al. added PTH(1-34) (400 U or 25 µ g/day) to 27 of 54 women receiving HRT for about 2 years (). During 3 years, spine fractures incidence was 37.5% (HRT alone) vs 8.3% (HRT + PTH) using 15% height reduction as a fracture criterion, or 25% vs 0% using 20% height reduction as a fracture criterion. BMD increased by 13.4% (spine), 4.4% (total hip), and 3.7% (total body). Caution is needed in interpreting the results; the fracture rates were high given that all patients received HRT.
Loss of the benefits of PTH after its withdrawalA critical issue with PTH administration is that the new bone formed at the axial and appendicular skeleton during PTH treatment appears to be lost when PTH is stopped (). However, not all animal studies report loss of effect (). Several questions need to be answered. (i) Are benefits are lost at both periosteal and endosteal surfaces? (ii) Is the extent of the loss of effect dependent on the dose, frequency and duration of administration? (iii) What are the effects of withdrawal of PTH in postmenopausal women? Based on data presented at the Endocrine Society in Denver this year, it does appear that the risk of fracture remained reduced when assessed at 20 months following cessation of PTH, and perhaps decreased even further for non-vertebral fractures. However, the veracity of the results cannot be evaluated until the work is published.
Antiresorptive therapy - after PTH?There is evidence that giving antiresorptive agents maintain the effects of PTH after it is withdrawn (). Ejersted et al. report that risedronate (5 µ g/kg/2 times/week for 8 weeks) maintained the higher MAR, BFR, cortical and trabecular bone area, and strength in 21 month old male rats (). Samnegard et al. ovariectomized rats and left them untreated for 11 weeks, an important design requirement when restoration of structure is being evaluated ().PTH(1-84) administered at 75 µ g/kg/d/3 times/week for 12 weeks was followed by risedronate (3 µ g/kg/3 days/week), or low dose PTH (25 µ g/kg/3 days/week). Benefits were maintained for 36 weeks using risedronate or low dose intermittent PTH. Similar benefits are seen using alendronate. Thomsen et al. treated 12 month old rats with the PTH analog, SDZ PTS 893 12 weeks after ovariectomy (). At 48 weeks, femoral diaphysis bone area increased by endosteal apposition. Ash density at L4 and the distal femoral metaphysis and bone strength decreased on withdrawal of the PTH analog but were maintained using alendronate (28 µ g/kg; 2 injections/week). In some of these studies estrogen and calcitonin appeared to be less effective than bisphosphonates, an observation that may be dose related ().
Sato et al. report that LY353381, a selective estrogen receptor modulator, and conjugated estrogen both maintain the benefits of PTH on cortical and trabecular bone after its withdrawal (). Six month old rats given 80 µ g/kg/day PTH(1-34) and LY117018 3 mg/kg/5 days per week for 12 weeks 1 month after ovariectomy then raloxifene alone, PTH (2 days/week) alone, or raloxifene plus PTH (2 or 5 days/week) for 2 months (). BMD increased and continued to rise in the group continuing raloxifene and PTH at 5 days/week. BMD was lost with PTH (2 days/week) or raloxifene alone but preserved with combined raloxifene and PTH (2 days/week). Maintenance of BMD was best achieved by combination PTH at reduced dosage with concurrent raloxifene analog.
In women with postmenopausal osteoporosis, Cosman et al. report that the women taking HRT plus PTH, the increase in BMD remained stable 1 year after discontinuation of PTH (). The inference that HRT maintains the PTH-induced increase in BMD may be correct, but design needed to assess this question was not ideal; there was no PTH alone group shown to lose bone following PTH withdrawal. Thus, studies in postmenopausal women are needed to test whether drugs like risedronate, alendronate, incadronate, raloxifene, or calcitonin maintain the effects of PTH at the axial and appendicular skeleton when it is withdrawn.
Antiresorptive therapy - before PTH?There does not appear to be an advantage in giving antiresorptives before PTH administration. In fact, pretreatment with alendronate may blunt the effect of PTH at the appendicular, not axial, skeleton in rats (). By contrast, no blunting of the effect of PTH was reported in rats pretreated with estrogen or clodronate. In the study by Cosman et al., the women were taking HRT for 2 years before PTH and there was an anabolic effect of PTH (). Whether it would have been greater with PTH alone cannot be determined as there was no control group given PTH alone
Antiresorptive therapy - during PTH?Antiresorptives given during PTH administration produce disparate observations. Sato et al. report that PTH plus LY353381 increased spine BMD above levels achieved with PTH alone or PTH plus estrogen (). PTH plus LY353381 increased BFR above PTH. This is not observed in other studies of antiresorptive drugs such as estrogen, risedronate, or calcitonin. Li et al. gave PTH with or without estradiol (4 days/week, 10 µ g/kg), risedronate (2 days/week, 5 µ g/kg) or calcitonin (4 days/week, 5 µ g/kg) to 15 month rats ovariectomized 12 months earlier (). PTH(1-34) alone (5 days/week, 80 µ g/kg) restored vertebral cancellous bone volume and strength. However, cotherapy did not augment the effects of PTH.
Qi et al. gave combined or single drug therapy for 10 weeks to four month rats 1 year after ovariectomy (). Cancellous osteopenia at the lumbar vertebra induced by ovariectomy was restored by PTH (80 µ g/kg 5 days/week) and partly so at the proximal tibial metaphysis. Risedronate (5 µ g/kg 2 days/wk) resulted in similar cancellous bone volume to vehicle treated ovariectomized rats; i.e., bone mass was maintained, not restored. PTH + risedronate restored lost bone to 53% of control levels. Hodsman et al. ovariectomized 6 month old rats and treated them 1 month later for 12 weeks with hPTH(1-34) (80 µg/kg/5 days/week), raloxifene (LY117018, 3 mg/kg/5 days/week), or both (). PTH increased BMD above ovariectomized and sham treated animals. Raloxifene did not increase BMD relative to ovariectomy alone. Animals receiving raloxifene plus PTH 5 times/week had higher BMD than sham animals. Raloxifene plus PTH 2 times/week increased BMD at all sites relative to ovariectomy alone but not over PTH alone; ie combined treatment is not better than PTH alone. The authors suggest that addition of raloxifene allowed reductions in PTH dosing frequency.
Likewise, in women with osteoporosis receiving 28 days of hPTH (800 U over 3 months) or PTH plus salmon calcitonin 75 U/day), no difference in BMD increment occurred at the spine (10.2% with PTH and 7.9% with PTH + calcitonin) (). At the femoral neck changes were 2.4% with PTH alone and decreased 1.8% (PTH + calcitonin). Vertebral fracture incidence (per 100 patient-years) was 4.5 (PTH alone) and 23 (PTH + calcitonin). In some studies there may be blunting of the effect of PTH. Concurrent tiludronate blunts the anabolic effect of PTH in the sheep (). The point is that generalizations are difficult to make and experimental evidence is needed for each drug to confirm whether combined treatment is beneficial or detrimental.
Intracortical porosity and incomplete matrix mineralizationIntracortical porosity is reported with intermittent PTH use, but most is located near the endocortical surface producing no deleterious biomechanical effects (). After withdrawal of PTH, porosity declined in the lower dose group but remained in higher dose group (). The clinical relevance of any intracortical porosity that may occur in humans using PTH is unknown. Nonvertebral fracture rates were reduced in the study by Neer et al. but nevertheless, whether increased porosity may compromise the strength of the proximal femur is unknown.
In addition, the increase in bone matrix is rapid and secondary mineralization may be incomplete. In the study of postmenopausal women, bone mineral content was unchanged despite the increase in bone mass, suggesting that PTH made new bone matrix but this may have not undergone complete secondary mineralization (). In the study by Kneissel et al. in rats, the average degree of mineralization of the bone was lowered, reflecting the increased portion of new bone formed (). In the study by Hirano et al. in rabbits, cancellous bone osteoid surface and volume, osteoblast surface, mineralizing surface and BFR increased but BMC and volumetric BMD were unchanged, perhaps because the new bone had undergone incomplete secondary mineralization (). Whether this continues to completion and may actually enhance bone strength further or may compromise bone strength is unknown.
The futureTherapy with PTH is a real advance, a chance to rebuild the skeleton's mass, reconstruct its architecture and so, restore the skeletons exquisite combination of lightness, elasticity and toughness. Characteristics essential in the lifelong battle against the evil forces of gravity which must be overcome when the remote control for the TV breaks down. Antispine and antihip fracture efficacy studies are needed in women and men with osteoporosis, and in patients with corticosteroid induced osteoporosis. An understanding is needed (i) of the effects of stopping PTH on bone structure, strength and fracture rates in humans, (ii) of adding antiresorptive drugs when treatment is withdrawn, (iii) of the most cost effective dose and duration of treatment with PTH, (iv) of the effects of other PTH fragments and (v) of how should PTH be placed in the approach to the patient. Many of these studies are underway, and the unresolved concerns are being addressed. This is an exciting time, full of new questions and new opportunities.
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